> top > docs > PMC:7594251 > spans > 1731-115737 > annotations

PMC:7594251 / 1731-115737 JSONTXT

Annnotations TAB JSON ListView MergeView

LitCovid_Glycan-Motif-Structure

Id Subject Object Predicate Lexical cue
T8612 15306-15313 https://glytoucan.org/Structures/Glycans/G15021LG denotes glucose
T44926 15430-15437 https://glytoucan.org/Structures/Glycans/G15021LG denotes glucose
T45962 63485-63505 https://glytoucan.org/Structures/Glycans/G64581RP denotes N-acetyl glucosamine
T71124 68783-68790 https://glytoucan.org/Structures/Glycans/G22418PV denotes (VIM)-2
T79079 68784-68787 https://glytoucan.org/Structures/Glycans/G00065MO denotes VIM
T6 92413-92420 https://glytoucan.org/Structures/Glycans/G15021LG denotes glucose
T7 92475-92482 https://glytoucan.org/Structures/Glycans/G15021LG denotes glucose

LitCovid-PD-FMA-UBERON

Id Subject Object Predicate Lexical cue fma_id
T1 98311-98318 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T2 98429-98436 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T3 98656-98663 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T4 98918-98925 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T5 99035-99042 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T6 99501-99508 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T7 99560-99567 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T8 99674-99681 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T9 99805-99812 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T10 99852-99859 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T11 100113-100123 Body_part denotes intestinal http://purl.org/sig/ont/fma/fma7199
T12 100124-100134 Body_part denotes fatty acid http://purl.org/sig/ont/fma/fma82738
T13 100143-100150 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T14 100305-100312 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T15 100465-100472 Body_part denotes Protein http://purl.org/sig/ont/fma/fma67257
T16 100553-100571 Body_part denotes proteins complexes http://purl.org/sig/ont/fma/fma67906
T17 100614-100621 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T18 100704-100711 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T19 100992-100998 Body_part denotes serine http://purl.org/sig/ont/fma/fma82764
T20 101650-101654 Body_part denotes Cell http://purl.org/sig/ont/fma/fma68646
T21 101704-101712 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T22 101810-101814 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T23 101920-101924 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T24 101953-101957 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T25 101992-101996 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T26 102060-102064 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T27 102126-102133 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T28 102135-102139 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T29 102287-102291 Body_part denotes Cell http://purl.org/sig/ont/fma/fma68646
T30 102361-102365 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T31 102560-102564 Body_part denotes Cell http://purl.org/sig/ont/fma/fma68646
T32 102595-102599 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T33 102675-102682 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T34 102706-102714 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T35 102750-102754 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T36 102832-102836 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T37 102905-102909 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T38 102943-102950 Body_part denotes oocytes http://purl.org/sig/ont/fma/fma18644
T39 102964-102969 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T40 102987-102992 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T41 103005-103010 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T42 103033-103038 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T43 103100-103104 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T44 103134-103138 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T45 103327-103335 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T46 103400-103407 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T47 103502-103509 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T48 103591-103613 Body_part denotes proteins and complexes http://purl.org/sig/ont/fma/fma67906
T49 103591-103599 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T50 103717-103724 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T51 103766-103770 Body_part denotes Cell http://purl.org/sig/ont/fma/fma68646
T52 103778-103782 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T53 103802-103810 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T54 103849-103852 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T55 103866-103879 Body_part denotes RNA molecules http://purl.org/sig/ont/fma/fma84126
T56 103866-103869 Body_part denotes RNA http://purl.org/sig/ont/fma/fma67095
T57 103957-103961 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T58 103998-104002 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T59 104332-104339 Body_part denotes histone http://purl.org/sig/ont/fma/fma74413
T60 104634-104642 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T61 104658-104663 Body_part denotes blood http://purl.org/sig/ont/fma/fma9670
T62 104723-104743 Body_part denotes scaffolding proteins http://purl.org/sig/ont/fma/fma62376
T63 104745-104748 Body_part denotes SPs http://purl.org/sig/ont/fma/fma62376
T64 104806-104814 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T65 104844-104852 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T66 104920-104923 Body_part denotes SPs http://purl.org/sig/ont/fma/fma62376
T67 105222-105239 Body_part denotes protein complexes http://purl.org/sig/ont/fma/fma67906
T68 105222-105229 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T69 105494-105498 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T70 105557-105565 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T71 105591-105599 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T72 105658-105663 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T73 105696-105704 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T74 110715-110717 Body_part denotes CS http://purl.org/sig/ont/fma/fma284995
T38790 3728-3735 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T60513 4736-4749 Body_part denotes aspartic acid http://purl.org/sig/ont/fma/fma82760
T80219 4825-4832 Body_part denotes neurons http://purl.org/sig/ont/fma/fma54527
T8361 5557-5565 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T10253 6964-6987 Body_part denotes transverse to the plane http://purl.org/sig/ont/fma/fma71928
T45898 7119-7135 Body_part denotes transverse plane http://purl.org/sig/ont/fma/fma71928
T76500 8590-8593 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T71803 8607-8615 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T51396 9234-9239 Body_part denotes urine http://purl.org/sig/ont/fma/fma12274
T52620 9244-9255 Body_part denotes blood serum http://purl.org/sig/ont/fma/fma63083
T43252 15306-15313 Body_part denotes glucose http://purl.org/sig/ont/fma/fma82743
T49086 15430-15437 Body_part denotes glucose http://purl.org/sig/ont/fma/fma82743
T48591 17555-17567 Body_part denotes phospholipid http://purl.org/sig/ont/fma/fma82779
T16532 17630-17633 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T27437 17787-17790 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T23683 18875-18880 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T17125 18917-18921 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T47161 21472-21477 Body_part denotes blood http://purl.org/sig/ont/fma/fma9670
T51661 21559-21564 Body_part denotes serum http://purl.org/sig/ont/fma/fma63083
T25681 21569-21574 Body_part denotes urine http://purl.org/sig/ont/fma/fma12274
T23891 22100-22105 Body_part denotes blood http://purl.org/sig/ont/fma/fma9670
T12355 24177-24183 Body_part denotes breast http://purl.org/sig/ont/fma/fma9601
T33062 24308-24313 Body_part denotes serum http://purl.org/sig/ont/fma/fma63083
T4462 24521-24526 Body_part denotes serum http://purl.org/sig/ont/fma/fma63083
T92872 24922-24927 Body_part denotes serum http://purl.org/sig/ont/fma/fma63083
T38324 24950-24956 Body_part denotes breast http://purl.org/sig/ont/fma/fma9601
T65570 26357-26362 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T64417 26466-26471 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T30907 26685-26690 Body_part denotes lipid http://purl.org/sig/ont/fma/fma67264
T71500 26757-26762 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T7498 26818-26823 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T49050 26901-26906 Body_part denotes lipid http://purl.org/sig/ont/fma/fma67264
T73203 26948-26953 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T75762 27119-27124 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T68385 27534-27542 Body_part denotes backbone http://purl.org/sig/ont/fma/fma13478
T68513 27546-27554 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T30146 28622-28627 Body_part denotes serum http://purl.org/sig/ont/fma/fma63083
T11099 28629-28635 Body_part denotes kidney http://purl.org/sig/ont/fma/fma7203
T30625 28641-28646 Body_part denotes liver http://purl.org/sig/ont/fma/fma7197
T37089 28647-28653 Body_part denotes tissue http://purl.org/sig/ont/fma/fma9637
T93967 29140-29150 Body_part denotes amino acid http://purl.org/sig/ont/fma/fma82739
T77772 29167-29172 Body_part denotes lipid http://purl.org/sig/ont/fma/fma67264
T43843 29226-29233 Body_part denotes kidneys http://purl.org/sig/ont/fma/fma7203
T96240 29238-29243 Body_part denotes liver http://purl.org/sig/ont/fma/fma7197
T49148 29632-29636 Body_part denotes axis http://purl.org/sig/ont/fma/fma12520
T36122 29981-29985 Body_part denotes axis http://purl.org/sig/ont/fma/fma12520
T39858 31734-31737 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T62847 32023-32030 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T88379 32307-32319 Body_part denotes blood plasma http://purl.org/sig/ont/fma/fma62970
T40091 32403-32410 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T37259 32515-32523 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T43243 34435-34443 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T42194 34639-34646 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T57538 35347-35351 Body_part denotes back http://purl.org/sig/ont/fma/fma25056
T52848 35436-35443 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T21500 36607-36614 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T80070 37342-37346 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T24520 37484-37488 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T39453 39927-39938 Body_part denotes lymphocytic http://purl.org/sig/ont/fma/fma62863
T84514 41280-41287 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T31879 42134-42142 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T80711 43670-43677 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T98872 44219-44227 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T86319 44494-44501 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T90624 45471-45478 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T33016 45593-45600 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T22016 46025-46028 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T39193 46033-46036 Body_part denotes RNA http://purl.org/sig/ont/fma/fma67095
T62167 47021-47028 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T15931 47151-47159 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T23445 47941-47948 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T55851 49241-49244 Body_part denotes RNA http://purl.org/sig/ont/fma/fma67095
T75217 49380-49387 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T89011 49514-49519 Body_part denotes blood http://purl.org/sig/ont/fma/fma9670
T17259 49636-49644 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T48151 50325-50333 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T14880 50371-50382 Body_part denotes amino acids http://purl.org/sig/ont/fma/fma82739
T73802 51186-51193 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T89652 51562-51569 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T76018 51816-51823 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T90230 51859-51867 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T69206 51992-51999 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T64359 52264-52279 Body_part denotes protein complex http://purl.org/sig/ont/fma/fma67906
T291 52758-52765 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T72984 52794-52798 Body_part denotes hand http://purl.org/sig/ont/fma/fma9712
T88588 53256-53263 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T33800 53810-53825 Body_part denotes polysaccharides http://purl.org/sig/ont/fma/fma82746
T79791 53872-53882 Body_part denotes E-selectin http://purl.org/sig/ont/fma/fma62932
T42543 53900-53907 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T16389 53922-53925 Body_part denotes IgG http://purl.org/sig/ont/fma/fma62872
T72564 54340-54347 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T83107 54937-54944 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T98493 55081-55088 Body_part denotes tubulin http://purl.org/sig/ont/fma/fma67116
T25827 55236-55251 Body_part denotes protein complex http://purl.org/sig/ont/fma/fma67906
T12583 55637-55644 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T45014 58374-58380 Body_part denotes radius http://purl.org/sig/ont/fma/fma23463
T35535 61439-61447 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T29116 62664-62671 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T42127 63485-63505 Body_part denotes N-acetyl glucosamine http://purl.org/sig/ont/fma/fma82787
T31376 63730-63735 Body_part denotes serum http://purl.org/sig/ont/fma/fma63083
T43729 64328-64335 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T41747 64336-64343 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T53232 65282-65289 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T29588 65346-65354 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T33707 66240-66243 Body_part denotes A2A http://purl.org/sig/ont/fma/fma68761
T71880 66271-66278 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T40803 67303-67310 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T15753 67441-67449 Body_part denotes cysteine http://purl.org/sig/ont/fma/fma82751
T4885 67451-67461 Body_part denotes amino acid http://purl.org/sig/ont/fma/fma82739
T7460 67770-67775 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T32139 68091-68095 Body_part denotes palm http://purl.org/sig/ont/fma/fma24920
T25080 68424-68431 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T54465 69272-69280 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T71697 69659-69666 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T41642 69707-69714 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T462 69805-69812 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T15051 70057-70065 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T29733 70430-70438 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T89089 70440-70443 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T83508 70449-70452 Body_part denotes RNA http://purl.org/sig/ont/fma/fma67095
T508 71918-71927 Body_part denotes protein’s http://purl.org/sig/ont/fma/fma67257
T64393 71948-71951 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T14796 72303-72310 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T31078 72332-72335 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T2567 72381-72384 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T82556 72561-72564 Body_part denotes DNA http://purl.org/sig/ont/fma/fma74412
T5753 72806-72814 Body_part denotes oxytocin http://purl.org/sig/ont/fma/fma74647
T78175 72819-72830 Body_part denotes vasopressin http://purl.org/sig/ont/fma/fma74646
T41120 72915-72923 Body_part denotes oxytocin http://purl.org/sig/ont/fma/fma74647
T81108 72928-72939 Body_part denotes vasopressin http://purl.org/sig/ont/fma/fma74646
T14848 73127-73135 Body_part denotes oxytocin http://purl.org/sig/ont/fma/fma74647
T92268 73140-73151 Body_part denotes vasopressin http://purl.org/sig/ont/fma/fma74646
T89759 73662-73669 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T97560 73682-73689 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T64825 73817-73824 Body_part denotes G-actin http://purl.org/sig/ont/fma/fma67893
T72415 73825-73832 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T78500 73838-73846 Body_part denotes thymosin http://purl.org/sig/ont/fma/fma67128
T87872 73854-73876 Body_part denotes actin- binding protein http://purl.org/sig/ont/fma/fma67119
T55142 74011-74018 Body_part denotes G-actin http://purl.org/sig/ont/fma/fma67893
T40518 74060-74064 Body_part denotes hand http://purl.org/sig/ont/fma/fma9712
T80287 74100-74107 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T51165 74194-74202 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T82421 74374-74382 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T145 74546-74553 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T146 74637-74645 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T147 74675-74682 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T148 75209-75217 Body_part denotes collagen http://purl.org/sig/ont/fma/fma63891
T149 75221-75226 Body_part denotes lipid http://purl.org/sig/ont/fma/fma67264
T150 75449-75457 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T151 77745-77753 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T152 78433-78441 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T153 79432-79437 Body_part denotes cells http://purl.org/sig/ont/fma/fma68646
T154 79442-79446 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T155 79465-79471 Body_part denotes breast http://purl.org/sig/ont/fma/fma9601
T156 79490-79494 Body_part denotes lung http://purl.org/sig/ont/fma/fma7195
T157 79817-79822 Body_part denotes sugar http://purl.org/sig/ont/fma/fma82737
T158 79840-79844 Body_part denotes cell http://purl.org/sig/ont/fma/fma68646
T159 80125-80132 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T160 80892-80901 Body_part denotes histidine http://purl.org/sig/ont/fma/fma82755
T161 80951-80961 Body_part denotes histidines http://purl.org/sig/ont/fma/fma82755
T162 82167-82174 Body_part denotes alanine http://purl.org/sig/ont/fma/fma82749
T163 82471-82478 Body_part denotes alanine http://purl.org/sig/ont/fma/fma82749
T164 82563-82570 Body_part denotes alanine http://purl.org/sig/ont/fma/fma82749
T165 83556-83563 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T166 83598-83605 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T167 83872-83879 Body_part denotes histone http://purl.org/sig/ont/fma/fma74413
T168 84510-84514 Body_part denotes sole http://purl.org/sig/ont/fma/fma25000
T169 85035-85038 Body_part denotes HIV http://purl.org/sig/ont/fma/fma278683
T170 85490-85501 Body_part denotes amino acids http://purl.org/sig/ont/fma/fma82739
T171 86104-86111 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T172 86112-86119 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T173 86343-86350 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T174 86351-86358 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T175 87363-87370 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T176 87575-87582 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T177 87878-87885 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T178 87886-87893 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T179 87964-87973 Body_part denotes protein’s http://purl.org/sig/ont/fma/fma67257
T180 88033-88041 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T181 89542-89549 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T182 89550-89557 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T183 90254-90257 Body_part denotes map http://purl.org/sig/ont/fma/fma67847
T184 90467-90474 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T185 90717-90724 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T186 90828-90830 Body_part denotes H4 http://purl.org/sig/ont/fma/fma84132
T187 90934-90936 Body_part denotes H3 http://purl.org/sig/ont/fma/fma84131
T188 91132-91135 Body_part denotes map http://purl.org/sig/ont/fma/fma67847
T189 91290-91297 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T190 91444-91447 Body_part denotes map http://purl.org/sig/ont/fma/fma67847
T191 91611-91618 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T192 92118-92125 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T193 92156-92164 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T194 92378-92383 Body_part denotes heart http://purl.org/sig/ont/fma/fma7088
T195 92413-92420 Body_part denotes glucose http://purl.org/sig/ont/fma/fma82743
T196 92475-92482 Body_part denotes glucose http://purl.org/sig/ont/fma/fma82743
T197 92757-92764 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T198 92834-92844 Body_part denotes amino acid http://purl.org/sig/ont/fma/fma82739
T199 92929-92939 Body_part denotes amino acid http://purl.org/sig/ont/fma/fma82739
T200 93015-93022 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T201 93065-93072 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T202 93330-93341 Body_part denotes amino acids http://purl.org/sig/ont/fma/fma82739
T203 93526-93537 Body_part denotes amino acids http://purl.org/sig/ont/fma/fma82739
T204 94100-94107 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T205 94300-94309 Body_part denotes protein’s http://purl.org/sig/ont/fma/fma67257
T206 94454-94471 Body_part denotes protein complexes http://purl.org/sig/ont/fma/fma67906
T207 94454-94461 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T208 94709-94717 Body_part denotes proteins http://purl.org/sig/ont/fma/fma67257
T209 94938-94945 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T210 95003-95010 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T211 95717-95724 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T212 96578-96585 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T213 96707-96714 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257
T214 96794-96801 Body_part denotes protein http://purl.org/sig/ont/fma/fma67257

LitCovid-PD-UBERON

Id Subject Object Predicate Lexical cue uberon_id
T1 9012-9016 Body_part denotes tube http://purl.obolibrary.org/obo/UBERON_0000025
T2 9020-9024 Body_part denotes tube http://purl.obolibrary.org/obo/UBERON_0000025
T3 9234-9239 Body_part denotes urine http://purl.obolibrary.org/obo/UBERON_0001088
T4 9244-9249 Body_part denotes blood http://purl.obolibrary.org/obo/UBERON_0000178
T5 9250-9255 Body_part denotes serum http://purl.obolibrary.org/obo/UBERON_0001977
T6 21472-21477 Body_part denotes blood http://purl.obolibrary.org/obo/UBERON_0000178
T7 21559-21564 Body_part denotes serum http://purl.obolibrary.org/obo/UBERON_0001977
T8 21569-21574 Body_part denotes urine http://purl.obolibrary.org/obo/UBERON_0001088
T9 22100-22105 Body_part denotes blood http://purl.obolibrary.org/obo/UBERON_0000178
T10 22305-22314 Body_part denotes extension http://purl.obolibrary.org/obo/UBERON_2000106
T11 24177-24183 Body_part denotes breast http://purl.obolibrary.org/obo/UBERON_0000310
T12 24308-24313 Body_part denotes serum http://purl.obolibrary.org/obo/UBERON_0001977
T13 24521-24526 Body_part denotes serum http://purl.obolibrary.org/obo/UBERON_0001977
T14 24922-24927 Body_part denotes serum http://purl.obolibrary.org/obo/UBERON_0001977
T15 24950-24956 Body_part denotes breast http://purl.obolibrary.org/obo/UBERON_0000310
T16 28622-28627 Body_part denotes serum http://purl.obolibrary.org/obo/UBERON_0001977
T17 28629-28635 Body_part denotes kidney http://purl.obolibrary.org/obo/UBERON_0002113
T18 28641-28646 Body_part denotes liver http://purl.obolibrary.org/obo/UBERON_0002107
T19 28647-28653 Body_part denotes tissue http://purl.obolibrary.org/obo/UBERON_0000479
T20 29238-29243 Body_part denotes liver http://purl.obolibrary.org/obo/UBERON_0002107
T21 32307-32319 Body_part denotes blood plasma http://purl.obolibrary.org/obo/UBERON_0001969
T22 32307-32312 Body_part denotes blood http://purl.obolibrary.org/obo/UBERON_0000178
T23 32601-32605 Body_part denotes Gill http://purl.obolibrary.org/obo/UBERON_0002535
T24 33257-33261 Body_part denotes Gill http://purl.obolibrary.org/obo/UBERON_0002535
T25 35499-35504 Body_part denotes scale http://purl.obolibrary.org/obo/UBERON_0002542
T26 49514-49519 Body_part denotes blood http://purl.obolibrary.org/obo/UBERON_0000178
T27 52794-52798 Body_part denotes hand http://purl.obolibrary.org/obo/UBERON_0002398
T28 59369-59373 Body_part denotes tube http://purl.obolibrary.org/obo/UBERON_0000025
T29 63730-63735 Body_part denotes serum http://purl.obolibrary.org/obo/UBERON_0001977
T30 74060-74064 Body_part denotes hand http://purl.obolibrary.org/obo/UBERON_0002398
T31 79465-79471 Body_part denotes breast http://purl.obolibrary.org/obo/UBERON_0000310
T32 79490-79494 Body_part denotes lung http://purl.obolibrary.org/obo/UBERON_0002048
T33 88452-88456 Body_part denotes Gill http://purl.obolibrary.org/obo/UBERON_0002535
T34 92378-92383 Body_part denotes heart http://purl.obolibrary.org/obo/UBERON_0000948
T35 104658-104663 Body_part denotes blood http://purl.obolibrary.org/obo/UBERON_0000178
T36 113423-113428 Body_part denotes scale http://purl.obolibrary.org/obo/UBERON_0002542

LitCovid-PD-MONDO

Id Subject Object Predicate Lexical cue mondo_id
T7 31-39 Disease denotes SARS-CoV http://purl.obolibrary.org/obo/MONDO_0005091
T8 42-50 Disease denotes COVID-19 http://purl.obolibrary.org/obo/MONDO_0100096
T9 4685-4704 Disease denotes Alzheimer’s disease http://purl.obolibrary.org/obo/MONDO_0004975
T10 4800-4807 Disease denotes amyloid http://purl.obolibrary.org/obo/MONDO_0019065
T11 4863-4882 Disease denotes Alzheimer’s disease http://purl.obolibrary.org/obo/MONDO_0004975
T12 24177-24190 Disease denotes breast cancer http://purl.obolibrary.org/obo/MONDO_0007254
T13 24184-24190 Disease denotes cancer http://purl.obolibrary.org/obo/MONDO_0004992
T14 24950-24963 Disease denotes breast cancer http://purl.obolibrary.org/obo/MONDO_0007254
T15 24957-24963 Disease denotes cancer http://purl.obolibrary.org/obo/MONDO_0004992
T16 26325-26342 Disease denotes ovarian carcinoma http://purl.obolibrary.org/obo/MONDO_0005140
T17 26333-26342 Disease denotes carcinoma http://purl.obolibrary.org/obo/MONDO_0004993
T18 28466-28468 Disease denotes HD http://purl.obolibrary.org/obo/MONDO_0007739
T19 31769-31772 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T20 31916-31918 Disease denotes he http://purl.obolibrary.org/obo/MONDO_0017319
T21 33764-33766 Disease denotes R2 http://purl.obolibrary.org/obo/MONDO_0019903
T22 36953-36956 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T23 37878-37881 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T24 37941-37944 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T25 38478-38481 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T26 38763-38766 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T27 39750-39756 Disease denotes cancer http://purl.obolibrary.org/obo/MONDO_0004992
T28 39838-39857 Disease denotes metastatic melanoma http://purl.obolibrary.org/obo/MONDO_0005191
T29 39849-39857 Disease denotes melanoma http://purl.obolibrary.org/obo/MONDO_0005105
T30 39919-39947 Disease denotes chronic lymphocytic leukemia http://purl.obolibrary.org/obo/MONDO_0004948
T31 39927-39947 Disease denotes lymphocytic leukemia http://purl.obolibrary.org/obo/MONDO_0005402
T32 39939-39947 Disease denotes leukemia http://purl.obolibrary.org/obo/MONDO_0005059
T33 42251-42254 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T34 42952-42955 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T35 43128-43131 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T36 43165-43168 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T37 44110-44113 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T38 44285-44288 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T39 44320-44323 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T40 45002-45005 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T41 45055-45058 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T42 45224-45227 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T43 45419-45422 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T44 45580-45583 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T45 45752-45755 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T46 46455-46458 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T47 46804-46807 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T48 46843-46846 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T49 47409-47412 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T50 47711-47714 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T51 48073-48076 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T52 48278-48281 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T53 48377-48380 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T54 48487-48490 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T55 48617-48620 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T56 49303-49318 Disease denotes gastroenteritis http://purl.obolibrary.org/obo/MONDO_0002269
T57 49577-49586 Disease denotes infection http://purl.obolibrary.org/obo/MONDO_0005550
T58 49713-49716 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T59 49966-49969 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T60 50396-50399 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T61 50621-50624 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T62 50836-50839 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T63 58970-58972 Disease denotes SE http://purl.obolibrary.org/obo/MONDO_0002125
T64 59015-59017 Disease denotes SE http://purl.obolibrary.org/obo/MONDO_0002125
T65 59060-59062 Disease denotes SE http://purl.obolibrary.org/obo/MONDO_0002125
T66 63269-63272 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T67 63393-63396 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T68 63656-63659 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T69 65019-65022 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T70 65078-65081 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T71 66315-66334 Disease denotes Parkinson’s disease http://purl.obolibrary.org/obo/MONDO_0005180
T72 67286-67291 Disease denotes tumor http://purl.obolibrary.org/obo/MONDO_0005070
T73 75462-75469 Disease denotes amyloid http://purl.obolibrary.org/obo/MONDO_0019065
T74 78222-78229 Disease denotes amyloid http://purl.obolibrary.org/obo/MONDO_0019065
T75 78293-78300 Disease denotes amyloid http://purl.obolibrary.org/obo/MONDO_0019065
T76 79425-79431 Disease denotes cancer http://purl.obolibrary.org/obo/MONDO_0004992
T77 79465-79478 Disease denotes breast cancer http://purl.obolibrary.org/obo/MONDO_0007254
T78 79472-79478 Disease denotes cancer http://purl.obolibrary.org/obo/MONDO_0004992
T79 79490-79501 Disease denotes lung cancer http://purl.obolibrary.org/obo/MONDO_0008903
T80 79495-79501 Disease denotes cancer http://purl.obolibrary.org/obo/MONDO_0004992
T81 80015-80022 Disease denotes amyloid http://purl.obolibrary.org/obo/MONDO_0019065
T82 80172-80179 Disease denotes amyloid http://purl.obolibrary.org/obo/MONDO_0019065
T83 80324-80331 Disease denotes amyloid http://purl.obolibrary.org/obo/MONDO_0019065
T84 81121-81124 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T85 82078-82081 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T86 82218-82230 Disease denotes tuberculosis http://purl.obolibrary.org/obo/MONDO_0018076
T87 82268-82271 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T88 82335-82338 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T89 82357-82360 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T90 82433-82436 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T91 82600-82603 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T92 82709-82712 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T93 82851-82854 Disease denotes ADC http://purl.obolibrary.org/obo/MONDO_0020689
T94 83256-83259 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T95 83701-83704 Disease denotes HTS http://purl.obolibrary.org/obo/MONDO_0011549
T96 83899-83902 Disease denotes HAT http://purl.obolibrary.org/obo/MONDO_0018048
T97 84014-84017 Disease denotes HAT http://purl.obolibrary.org/obo/MONDO_0018048
T98 84153-84156 Disease denotes HAT http://purl.obolibrary.org/obo/MONDO_0018048
T99 85009-85025 Disease denotes immunodeficiency http://purl.obolibrary.org/obo/MONDO_0021094
T100 86398-86404 Disease denotes cancer http://purl.obolibrary.org/obo/MONDO_0004992
T101 88061-88064 Disease denotes VHL http://purl.obolibrary.org/obo/MONDO_0008667
T102 88425-88428 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T103 88710-88713 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T104 90036-90039 Disease denotes CSP http://purl.obolibrary.org/obo/MONDO_0005078
T105 90302-90305 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T106 92574-92577 Disease denotes SOS http://purl.obolibrary.org/obo/MONDO_0011604
T107 92676-92679 Disease denotes SOS http://purl.obolibrary.org/obo/MONDO_0011604
T108 92696-92699 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T109 92883-92886 Disease denotes SOS http://purl.obolibrary.org/obo/MONDO_0011604
T110 93628-93631 Disease denotes SOS http://purl.obolibrary.org/obo/MONDO_0011604
T111 93730-93733 Disease denotes SOS http://purl.obolibrary.org/obo/MONDO_0011604
T112 95044-95050 Disease denotes dengue http://purl.obolibrary.org/obo/MONDO_0005502
T113 95062-95065 Disease denotes NS3 http://purl.obolibrary.org/obo/MONDO_0012371
T114 99491-99494 Disease denotes CSP http://purl.obolibrary.org/obo/MONDO_0005078
T115 99510-99513 Disease denotes CSP http://purl.obolibrary.org/obo/MONDO_0005078
T116 99658-99661 Disease denotes CSP http://purl.obolibrary.org/obo/MONDO_0005078
T117 100023-100026 Disease denotes CSP http://purl.obolibrary.org/obo/MONDO_0005078
T118 100424-100427 Disease denotes CSP http://purl.obolibrary.org/obo/MONDO_0005078
T119 102296-102299 Disease denotes STD http://purl.obolibrary.org/obo/MONDO_0021681
T120 110456-110459 Disease denotes MDD http://purl.obolibrary.org/obo/MONDO_0012048|http://purl.obolibrary.org/obo/MONDO_0016217

LitCovid-PD-CLO

Id Subject Object Predicate Lexical cue
T355 49245-49252 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes viruses
T356 49371-49372 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T357 49415-49416 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T358 49487-49492 http://purl.obolibrary.org/obo/NCBITaxon_9606 denotes human
T359 49514-49519 http://purl.obolibrary.org/obo/UBERON_0000178 denotes blood
T360 49514-49519 http://www.ebi.ac.uk/efo/EFO_0000296 denotes blood
T361 49856-49857 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T362 49863-49864 http://purl.obolibrary.org/obo/CLO_0001021 denotes B
T363 49891-49896 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T364 49922-49923 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T365 49994-49995 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T366 50274-50275 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T367 50431-50432 http://purl.obolibrary.org/obo/CLO_0001021 denotes B
T368 50693-50696 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T369 50792-50798 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T370 51226-51227 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T371 51291-51293 http://www.ebi.ac.uk/efo/EFO_0000265 denotes Da
T372 51560-51561 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T373 51731-51732 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T374 51791-51798 http://purl.obolibrary.org/obo/SO_0000418 denotes Signals
T375 51933-51934 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T376 52000-52007 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T377 52043-52045 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T378 52264-52279 http://purl.obolibrary.org/obo/GO_0043234 denotes protein complex
T379 52505-52506 http://purl.obolibrary.org/obo/CLO_0001021 denotes b
T380 52622-52623 http://purl.obolibrary.org/obo/CLO_0001021 denotes b
T381 52714-52715 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T382 52928-52929 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T383 53233-53234 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T384 53245-53246 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T385 53548-53550 http://purl.obolibrary.org/obo/CLO_0007874 denotes ms
T386 53696-53704 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T387 53776-53777 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T388 53898-53899 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T389 53939-53940 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T390 54392-54398 http://purl.obolibrary.org/obo/CLO_0054057 denotes 1, 8:1
T391 54400-54404 http://purl.obolibrary.org/obo/CLO_0001053 denotes 12:1
T392 54419-54424 http://purl.obolibrary.org/obo/CLO_0001757 denotes 1, at
T393 54815-54816 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T394 55060-55061 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T395 55104-55105 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T396 55227-55228 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T397 55236-55251 http://purl.obolibrary.org/obo/GO_0043234 denotes protein complex
T398 55380-55381 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T399 55733-55734 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T400 55860-55861 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T401 55889-55890 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T402 55895-55896 http://purl.obolibrary.org/obo/CLO_0001021 denotes B
T403 55986-55987 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T404 55992-55993 http://purl.obolibrary.org/obo/CLO_0001021 denotes B
T405 56025-56026 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T406 56121-56122 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T407 56127-56128 http://purl.obolibrary.org/obo/CLO_0001021 denotes B
T408 56262-56263 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T409 56345-56347 http://purl.obolibrary.org/obo/CLO_0004265 denotes HT
T410 56480-56481 http://purl.obolibrary.org/obo/CLO_0001021 denotes B
T411 56587-56589 http://purl.obolibrary.org/obo/CLO_0004265 denotes HT
T412 56636-56638 http://purl.obolibrary.org/obo/CLO_0003622 denotes HB
T413 56643-56644 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T414 56687-56689 http://purl.obolibrary.org/obo/CLO_0003622 denotes HB
T415 56740-56741 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T416 57049-57050 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T417 57157-57158 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T418 57277-57278 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T419 57414-57415 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T420 57454-57456 http://purl.obolibrary.org/obo/CLO_0053733 denotes 11
T421 57592-57593 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T422 57610-57611 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T423 57644-57645 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T424 57739-57740 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T425 57900-57901 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T426 58224-58226 http://purl.obolibrary.org/obo/CLO_0008882 denotes rs
T427 58234-58236 http://purl.obolibrary.org/obo/CLO_0007074 denotes kb
T428 58234-58236 http://purl.obolibrary.org/obo/CLO_0051988 denotes kb
T429 58351-58353 http://purl.obolibrary.org/obo/CLO_0008882 denotes rs
T430 59005-59008 http://purl.obolibrary.org/obo/CLO_0001230 denotes 293
T431 59005-59008 http://purl.obolibrary.org/obo/CLO_0037237 denotes 293
T432 59005-59008 http://purl.obolibrary.org/obo/CLO_0050903 denotes 293
T433 59005-59008 http://purl.obolibrary.org/obo/CLO_0054249 denotes 293
T434 59005-59008 http://purl.obolibrary.org/obo/CLO_0054250 denotes 293
T435 59005-59008 http://purl.obolibrary.org/obo/CLO_0054251 denotes 293
T436 59005-59008 http://purl.obolibrary.org/obo/CLO_0054252 denotes 293
T1 98149-98150 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T2 98188-98189 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T3 98212-98213 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T4 98233-98234 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T5 98398-98399 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T6 98497-98504 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T7 98727-98729 http://purl.obolibrary.org/obo/CLO_0002960 denotes F1
T8 98777-98778 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T9 98901-98902 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T10 99033-99034 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T11 99499-99500 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T12 99558-99559 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T13 99665-99666 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T14 99697-99698 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T15 99734-99735 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T16 99796-99804 http://purl.obolibrary.org/obo/CLO_0007225 denotes labelled
T17 99921-99926 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T18 100107-100112 http://purl.obolibrary.org/obo/NCBITaxon_9606 denotes human
T19 100113-100123 http://purl.obolibrary.org/obo/UBERON_0000160 denotes intestinal
T20 100113-100123 http://www.ebi.ac.uk/efo/EFO_0000834 denotes intestinal
T21 100485-100493 http://www.ebi.ac.uk/efo/EFO_0000876 denotes Extremes
T22 100553-100571 http://purl.obolibrary.org/obo/GO_0043234 denotes proteins complexes
T23 100702-100703 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T24 100752-100753 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T25 100797-100798 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T26 100848-100849 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T27 100933-100939 http://purl.obolibrary.org/obo/UBERON_0000473 denotes tested
T28 101416-101419 http://purl.obolibrary.org/obo/CLO_0001195 denotes 219
T29 101650-101654 http://purl.obolibrary.org/obo/GO_0005623 denotes Cell
T30 101810-101814 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T31 101920-101924 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T32 101953-101957 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T33 101992-101996 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T34 102060-102064 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T35 102107-102114 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T36 102135-102139 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T37 102187-102188 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T38 102287-102291 http://purl.obolibrary.org/obo/GO_0005623 denotes Cell
T39 102307-102308 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T40 102361-102365 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T41 102406-102415 http://purl.obolibrary.org/obo/CLO_0007225 denotes labelling
T42 102458-102467 http://purl.obolibrary.org/obo/CLO_0007225 denotes labelling
T43 102560-102564 http://purl.obolibrary.org/obo/GO_0005623 denotes Cell
T44 102595-102599 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T45 102648-102655 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T46 102667-102674 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T47 102735-102742 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T48 102750-102754 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T49 102832-102841 http://purl.obolibrary.org/obo/CL_0000000 denotes cell type
T50 102850-102858 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T51 102905-102915 http://purl.obolibrary.org/obo/CL_0000000 denotes cell types
T52 102927-102935 http://purl.obolibrary.org/obo/NCBITaxon_2 denotes bacteria
T53 102952-102955 http://purl.obolibrary.org/obo/CLO_0001360 denotes 412
T54 102964-102969 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T55 102987-102992 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T56 103000-103010 http://purl.obolibrary.org/obo/CLO_0054283 denotes HeLa cells
T57 103000-103010 http://purl.obolibrary.org/obo/CLO_0054285 denotes HeLa cells
T58 103000-103010 http://purl.obolibrary.org/obo/CLO_0054286 denotes HeLa cells
T59 103000-103010 http://purl.obolibrary.org/obo/CLO_0054287 denotes HeLa cells
T60 103000-103010 http://purl.obolibrary.org/obo/CLO_0054288 denotes HeLa cells
T61 103000-103010 http://purl.obolibrary.org/obo/CLO_0054289 denotes HeLa cells
T62 103000-103004 http://purl.obolibrary.org/obo/CLO_0003684 denotes HeLa
T63 103000-103004 http://purl.obolibrary.org/obo/CLO_0050910 denotes HeLa
T64 103033-103038 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T65 103100-103104 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T66 103134-103143 http://purl.obolibrary.org/obo/CL_0000000 denotes cell type
T67 103230-103238 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T68 103351-103359 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T69 103360-103363 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T70 103381-103382 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T71 103591-103613 http://purl.obolibrary.org/obo/GO_0043234 denotes proteins and complexes
T72 103642-103650 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T73 103766-103770 http://purl.obolibrary.org/obo/GO_0005623 denotes Cell
T74 103778-103782 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T75 103816-103819 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T76 103957-103961 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T77 103998-104002 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T78 104030-104036 http://purl.obolibrary.org/obo/CLO_0007225 denotes labels
T79 104083-104084 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T80 104320-104328 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T81 104407-104414 http://purl.obolibrary.org/obo/PR_000018263 denotes peptide
T82 104443-104449 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T83 104535-104536 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T84 104652-104657 http://purl.obolibrary.org/obo/NCBITaxon_9606 denotes human
T85 104658-104663 http://purl.obolibrary.org/obo/UBERON_0000178 denotes blood
T86 104658-104663 http://www.ebi.ac.uk/efo/EFO_0000296 denotes blood
T87 104675-104680 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes Virus
T88 104703-104710 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes viruses
T89 104745-104748 http://purl.obolibrary.org/obo/CLO_0009124 denotes SPs
T90 104785-104797 http://purl.obolibrary.org/obo/OBI_0000245 denotes organization
T91 104858-104859 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T92 104881-104889 http://purl.obolibrary.org/obo/PR_000001898 denotes called a
T93 104920-104923 http://purl.obolibrary.org/obo/CLO_0009124 denotes SPs
T94 105039-105040 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T95 105147-105148 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T96 105222-105239 http://purl.obolibrary.org/obo/GO_0043234 denotes protein complexes
T97 105270-105271 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T98 105494-105498 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T99 105538-105545 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T100 105658-105663 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T101 105688-105695 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T102 105759-105778 http://purl.obolibrary.org/obo/GO_0005575 denotes cellular components
T103 105813-105818 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T104 105965-105970 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T105 106159-106164 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T106 106291-106294 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T107 106295-106296 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T108 106389-106390 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T109 106474-106475 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T110 106582-106588 http://purl.obolibrary.org/obo/UBERON_0007688 denotes fields
T111 106931-106938 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T112 107238-107239 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T113 107554-107555 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T114 107776-107781 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T115 107805-107806 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T116 107842-107847 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T117 108043-108048 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T118 108069-108072 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T119 108189-108200 http://purl.obolibrary.org/obo/OBI_0000968 denotes instruments
T120 108345-108351 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T121 108911-108912 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T122 108993-108994 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T123 109264-109265 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T124 109284-109285 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T125 109584-109587 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T126 109881-109887 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T127 109914-109915 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T128 110236-110242 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T129 110612-110618 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T130 110827-110832 http://purl.obolibrary.org/obo/CLO_0009985 denotes focus
T131 110915-110921 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T132 111338-111339 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T133 111890-111900 http://purl.obolibrary.org/obo/OBI_0000968 denotes instrument
T134 113121-113127 http://purl.obolibrary.org/obo/SO_0000418 denotes Signal
T135 113274-113277 http://purl.obolibrary.org/obo/CLO_0001375 denotes 455
T136 113300-113303 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T137 113311-113312 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T138 113547-113555 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T139 113590-113593 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T140 113605-113606 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T141 113929-113932 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T11156 71-73 http://purl.obolibrary.org/obo/CLO_0001302 denotes 34
T1321 167-168 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T20418 459-460 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T33210 470-473 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T56537 538-539 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T14710 797-798 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T5958 818-825 http://purl.obolibrary.org/obo/UBERON_0000473 denotes testing
T70818 871-872 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T2693 1097-1098 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T73848 1297-1298 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T46124 2147-2150 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T768 2151-2160 http://www.ebi.ac.uk/efo/EFO_0000876 denotes extremely
T84574 3245-3246 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T27515 3611-3614 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T97004 4151-4154 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T26399 4550-4552 http://purl.obolibrary.org/obo/CLO_0001313 denotes 36
T10521 4716-4717 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T91269 4718-4726 http://purl.obolibrary.org/obo/UBERON_0000158 denotes membrane
T7501 4800-4821 http://purl.obolibrary.org/obo/PR_000036193 denotes amyloid beta peptides
T15351 5066-5067 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T61451 5252-5254 http://purl.obolibrary.org/obo/CLO_0001313 denotes 36
T78635 5265-5266 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T85737 5595-5598 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T68234 5744-5745 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T99227 5778-5780 http://purl.obolibrary.org/obo/CLO_0054055 denotes 71
T43341 5988-5989 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T23700 6051-6052 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T82249 6400-6401 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T85549 6443-6448 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T55590 6550-6555 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T58445 6557-6558 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T92263 6718-6723 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T68728 6861-6866 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T45061 6906-6912 http://purl.obolibrary.org/obo/UBERON_0007688 denotes fields
T88556 7011-7016 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T91683 7206-7207 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T21171 7349-7355 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T51401 7359-7360 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T56863 7413-7420 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T47125 7619-7624 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T12208 7850-7851 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T78536 7902-7908 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T91135 7965-7971 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T25038 8031-8037 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T74964 8451-8454 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T81620 8474-8475 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T92233 8680-8683 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T76872 8885-8887 http://purl.obolibrary.org/obo/CLO_0007874 denotes MS
T13161 8972-8974 http://purl.obolibrary.org/obo/CLO_0007874 denotes MS
T45199 9012-9016 http://purl.obolibrary.org/obo/UBERON_0000025 denotes tube
T90327 9020-9024 http://purl.obolibrary.org/obo/UBERON_0000025 denotes tube
T28659 9156-9158 http://purl.obolibrary.org/obo/CLO_0007874 denotes MS
T4970 9244-9249 http://purl.obolibrary.org/obo/UBERON_0000178 denotes blood
T39983 9244-9249 http://www.ebi.ac.uk/efo/EFO_0000296 denotes blood
T71596 9339-9341 http://purl.obolibrary.org/obo/CL_0000453 denotes LC
T60852 9344-9346 http://purl.obolibrary.org/obo/CLO_0007874 denotes MS
T71533 9816-9819 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T11494 10003-10004 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T62411 10088-10089 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T22590 10090-10096 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T23235 10417-10426 http://www.ebi.ac.uk/efo/EFO_0000876 denotes extremely
T66345 10471-10474 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T3179 10475-10476 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T38441 10562-10571 http://www.ebi.ac.uk/efo/EFO_0000876 denotes extremely
T85356 10661-10662 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T55626 10743-10744 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T7693 10988-10991 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T74928 11058-11064 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T89386 11094-11095 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T25318 11119-11129 http://purl.obolibrary.org/obo/UBERON_0003103 denotes in organic
T33905 11670-11671 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T68532 11690-11695 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T34126 11899-11902 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T31583 11903-11904 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T16829 11938-11945 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T20933 11978-11984 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T99257 12164-12170 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T77549 12355-12361 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T61613 12390-12391 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T96943 12582-12583 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T55349 12669-12670 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T77383 12685-12690 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T73188 12730-12731 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T78366 12783-12788 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T25547 13044-13045 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T31964 13113-13114 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T20822 13223-13224 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T63367 13412-13418 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T91886 13523-13524 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T73157 13665-13668 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T7374 13818-13825 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T55495 13833-13834 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T28108 13929-13932 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T85300 14071-14074 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T32942 14075-14076 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T90006 14542-14548 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T67222 14592-14593 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T67710 14930-14931 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T9295 15059-15060 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T92474 15496-15502 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T45804 15709-15712 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T42617 15713-15714 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T69056 15891-15892 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T13009 16024-16025 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T53392 16157-16158 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T47108 16204-16205 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T33086 16278-16285 http://purl.obolibrary.org/obo/CLO_0009985 denotes focuses
T45570 16375-16381 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T41073 16388-16389 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T98684 16492-16500 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T86896 16523-16526 http://purl.obolibrary.org/obo/CLO_0053001 denotes 114
T1229 16867-16873 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T1088 16890-16896 http://purl.obolibrary.org/obo/SO_0000418 denotes Signal
T92599 17138-17139 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T87879 17170-17171 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T52531 17465-17466 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T49797 17812-17820 http://purl.obolibrary.org/obo/NCBITaxon_2 denotes bacteria
T79755 17822-17824 http://purl.obolibrary.org/obo/CLO_0001527 denotes 94
T36380 17923-17924 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T78941 17973-17975 http://purl.obolibrary.org/obo/PR_000005794 denotes CP
T26738 18077-18078 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T50950 18125-18133 http://purl.obolibrary.org/obo/NCBITaxon_2 denotes bacteria
T83068 18176-18184 http://purl.obolibrary.org/obo/NCBITaxon_2 denotes bacteria
T72911 18230-18236 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T66455 18276-18277 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T71611 18395-18397 http://purl.obolibrary.org/obo/CLO_0001527 denotes 94
T15967 18497-18505 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T47909 18791-18794 http://purl.obolibrary.org/obo/CLO_0001053 denotes 121
T76054 18875-18880 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T47371 18917-18921 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T39170 19316-19321 http://purl.obolibrary.org/obo/CLO_0009985 denotes focus
T60635 19424-19425 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T17528 19874-19875 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T92439 19909-19910 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T83859 19941-19942 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T91246 19969-19970 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T69709 19991-19993 http://purl.obolibrary.org/obo/CLO_0050160 denotes t2
T91898 20078-20080 http://purl.obolibrary.org/obo/CLO_0053799 denotes 45
T92124 20173-20175 http://purl.obolibrary.org/obo/CLO_0053799 denotes 45
T26137 20223-20224 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T63635 20260-20262 http://purl.obolibrary.org/obo/CLO_0003401 denotes FT
T78725 21117-21118 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T76502 21129-21132 http://purl.obolibrary.org/obo/CLO_0054061 denotes 132
T42866 21472-21477 http://purl.obolibrary.org/obo/UBERON_0000178 denotes blood
T98943 21472-21477 http://www.ebi.ac.uk/efo/EFO_0000296 denotes blood
T84919 21823-21825 http://purl.obolibrary.org/obo/CLO_0050510 denotes 18
T56516 21925-21926 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T86496 22100-22105 http://purl.obolibrary.org/obo/UBERON_0000178 denotes blood
T59085 22100-22105 http://www.ebi.ac.uk/efo/EFO_0000296 denotes blood
T91276 22399-22400 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T16293 22566-22567 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T61631 22651-22652 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T75997 22676-22677 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T45961 22932-22933 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T2549 23012-23013 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T36623 23045-23046 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T51654 23329-23330 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T1722 23819-23820 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T27590 24177-24183 http://purl.obolibrary.org/obo/UBERON_0000310 denotes breast
T45515 24950-24956 http://purl.obolibrary.org/obo/UBERON_0000310 denotes breast
T6025 25032-25033 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T92227 25979-25986 http://purl.obolibrary.org/obo/OBI_0100026 denotes organic
T84020 25979-25986 http://purl.obolibrary.org/obo/UBERON_0000468 denotes organic
T7565 26314-26324 http://purl.obolibrary.org/obo/CL_0000066 denotes epithelial
T25877 26350-26356 http://purl.obolibrary.org/obo/CLO_0009063 denotes Skov-3
T65918 26350-26356 http://purl.obolibrary.org/obo/CLO_0052004 denotes Skov-3
T15262 26350-26356 http://purl.obolibrary.org/obo/CLO_0052005 denotes Skov-3
T84733 26350-26356 http://purl.obolibrary.org/obo/CLO_0052006 denotes Skov-3
T563 26350-26356 http://purl.obolibrary.org/obo/CLO_0052007 denotes Skov-3
T68261 26357-26362 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T18385 26459-26465 http://purl.obolibrary.org/obo/CLO_0009063 denotes Skov-3
T7784 26459-26465 http://purl.obolibrary.org/obo/CLO_0052004 denotes Skov-3
T18201 26459-26465 http://purl.obolibrary.org/obo/CLO_0052005 denotes Skov-3
T44166 26459-26465 http://purl.obolibrary.org/obo/CLO_0052006 denotes Skov-3
T15184 26459-26465 http://purl.obolibrary.org/obo/CLO_0052007 denotes Skov-3
T72019 26466-26471 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T67725 26622-26627 http://purl.obolibrary.org/obo/NCBITaxon_9606 denotes Human
T49059 26750-26756 http://purl.obolibrary.org/obo/CLO_0009063 denotes Skov-3
T24432 26750-26756 http://purl.obolibrary.org/obo/CLO_0052004 denotes Skov-3
T13031 26750-26756 http://purl.obolibrary.org/obo/CLO_0052005 denotes Skov-3
T58426 26750-26756 http://purl.obolibrary.org/obo/CLO_0052006 denotes Skov-3
T52203 26750-26756 http://purl.obolibrary.org/obo/CLO_0052007 denotes Skov-3
T21105 26757-26762 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T98431 26811-26817 http://purl.obolibrary.org/obo/CLO_0009063 denotes Skov-3
T53038 26811-26817 http://purl.obolibrary.org/obo/CLO_0052004 denotes Skov-3
T12991 26811-26817 http://purl.obolibrary.org/obo/CLO_0052005 denotes Skov-3
T66845 26811-26817 http://purl.obolibrary.org/obo/CLO_0052006 denotes Skov-3
T99568 26811-26817 http://purl.obolibrary.org/obo/CLO_0052007 denotes Skov-3
T50576 26818-26823 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T80995 26948-26953 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T54819 27030-27031 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T69803 27112-27118 http://purl.obolibrary.org/obo/CLO_0009063 denotes Skov-3
T3282 27112-27118 http://purl.obolibrary.org/obo/CLO_0052004 denotes Skov-3
T25858 27112-27118 http://purl.obolibrary.org/obo/CLO_0052005 denotes Skov-3
T4936 27112-27118 http://purl.obolibrary.org/obo/CLO_0052006 denotes Skov-3
T20172 27112-27118 http://purl.obolibrary.org/obo/CLO_0052007 denotes Skov-3
T80018 27119-27124 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T84214 27556-27559 http://purl.obolibrary.org/obo/CLO_0001079 denotes 148
T6479 27733-27734 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T20389 28076-28077 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T21966 28231-28232 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T74078 28427-28429 http://purl.obolibrary.org/obo/CLO_0007622 denotes MD
T25528 28492-28493 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T81398 28629-28635 http://purl.obolibrary.org/obo/UBERON_0002113 denotes kidney
T40369 28629-28635 http://www.ebi.ac.uk/efo/EFO_0000927 denotes kidney
T23231 28629-28635 http://www.ebi.ac.uk/efo/EFO_0000929 denotes kidney
T2572 28641-28646 http://purl.obolibrary.org/obo/UBERON_0002107 denotes liver
T95714 28641-28646 http://www.ebi.ac.uk/efo/EFO_0000887 denotes liver
T49055 28835-28842 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T39599 29079-29080 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T14589 29226-29233 http://purl.obolibrary.org/obo/UBERON_0002113 denotes kidneys
T43132 29226-29233 http://www.ebi.ac.uk/efo/EFO_0000927 denotes kidneys
T76931 29226-29233 http://www.ebi.ac.uk/efo/EFO_0000929 denotes kidneys
T29795 29238-29243 http://purl.obolibrary.org/obo/UBERON_0002107 denotes liver
T14410 29238-29243 http://www.ebi.ac.uk/efo/EFO_0000887 denotes liver
T94198 29309-29310 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T56129 29365-29371 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T5556 29464-29465 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T92788 29919-29921 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T84489 30035-30036 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T58840 30078-30080 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T62015 30191-30193 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T43160 30371-30373 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T17546 30538-30539 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T33912 30578-30579 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T82452 30834-30840 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T73705 30869-30875 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T4765 30887-30890 http://purl.obolibrary.org/obo/CLO_0001002 denotes 162
T99665 31277-31278 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T91826 31287-31290 http://purl.obolibrary.org/obo/CLO_0001003 denotes 163
T95563 31316-31317 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T10689 31391-31392 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T87448 31757-31758 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T90168 32307-32319 http://purl.obolibrary.org/obo/UBERON_0001969 denotes blood plasma
T40421 32535-32537 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T16944 32601-32605 http://purl.obolibrary.org/obo/UBERON_0002535 denotes Gill
T99850 32722-32723 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T53426 32745-32746 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T70539 32792-32793 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T40931 33005-33006 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T32172 33257-33261 http://purl.obolibrary.org/obo/UBERON_0002535 denotes Gill
T47725 33425-33427 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T26340 33671-33677 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T37945 33695-33696 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T67693 33809-33815 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T74144 33825-33826 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T61672 33839-33840 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T776 33925-33926 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T90184 33943-33949 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T29187 33973-33975 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T80855 34056-34058 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T17769 34060-34062 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T1564 34157-34162 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T88676 34242-34244 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T90343 34323-34324 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T92264 34345-34347 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T51742 34559-34561 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T65081 34826-34827 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T76730 34906-34908 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T85793 35125-35127 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T71306 35903-35904 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T274 36019-36020 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T275 36058-36059 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T276 36140-36147 http://purl.obolibrary.org/obo/OBI_0100026 denotes organic
T277 36140-36147 http://purl.obolibrary.org/obo/UBERON_0000468 denotes organic
T278 36157-36160 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T279 36489-36492 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T280 36568-36571 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T281 36728-36729 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T282 36754-36762 http://purl.obolibrary.org/obo/CLO_0001658 denotes Activity
T283 37078-37080 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T284 37342-37346 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T285 37484-37488 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T286 37766-37767 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T287 37969-37970 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T288 38095-38096 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T289 38145-38146 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T290 38482-38485 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T291 38785-38786 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T292 38826-38827 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T293 38852-38853 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T294 38894-38895 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T295 38999-39000 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T296 39877-39878 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T297 39949-39952 http://purl.obolibrary.org/obo/CLO_0001196 denotes 225
T298 40049-40050 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T299 40583-40591 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T300 40698-40707 http://www.ebi.ac.uk/efo/EFO_0000876 denotes extremely
T301 40832-40833 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T302 41545-41546 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T303 41610-41611 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T304 42890-42893 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T305 43083-43085 http://purl.obolibrary.org/obo/CLO_0050160 denotes T2
T306 43521-43522 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T307 43614-43615 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T308 43668-43669 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T309 43779-43780 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T310 43856-43857 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T311 43905-43911 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T312 43984-43992 http://purl.obolibrary.org/obo/PR_000001898 denotes called a
T313 44081-44087 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T314 44183-44184 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T315 44235-44236 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T316 44364-44365 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T317 44389-44390 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T318 44509-44512 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T319 44513-44514 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T320 44565-44566 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T321 44577-44583 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T322 44589-44590 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T323 44646-44652 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T324 44704-44705 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T325 44706-44712 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T326 44748-44749 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T327 44985-44986 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T328 45094-45100 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T329 45591-45592 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T330 45858-45864 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T331 45973-45976 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T332 46348-46351 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T333 46583-46588 http://purl.obolibrary.org/obo/NCBITaxon_9606 denotes human
T334 46723-46730 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes viruses
T335 46736-46737 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T336 47005-47013 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T337 47039-47042 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T338 47185-47190 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T339 47287-47292 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T340 47348-47355 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes viruses
T341 47456-47461 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T342 47574-47579 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T343 47653-47660 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes viruses
T344 47800-47805 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T345 47899-47900 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T346 47901-47906 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T347 48036-48039 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T348 48152-48157 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T349 48217-48218 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T350 48345-48346 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T351 48705-48712 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes viruses
T352 48751-48756 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T353 48829-48830 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T354 49101-49102 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T437 59083-59084 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T438 59133-59138 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T439 59148-59153 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T440 59273-59279 http://purl.obolibrary.org/obo/CLO_0007225 denotes labels
T441 59308-59314 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T442 59369-59373 http://purl.obolibrary.org/obo/UBERON_0000025 denotes tube
T443 59503-59510 http://purl.obolibrary.org/obo/CLO_0009985 denotes focuses
T444 59550-59551 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T445 59552-59558 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T446 59585-59586 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T447 59666-59674 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T448 59682-59688 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T449 59707-59708 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T450 59931-59937 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T451 60049-60051 http://purl.obolibrary.org/obo/CLO_0003414 denotes g2
T452 60131-60137 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T453 60410-60416 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T454 60614-60615 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T455 60981-60982 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T456 61096-61099 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T457 61530-61538 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T458 61651-61658 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T459 61712-61713 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T460 61807-61814 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T461 61883-61890 http://purl.obolibrary.org/obo/SO_0000418 denotes signals
T462 61996-61997 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T463 62275-62281 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T464 62890-62891 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T465 62909-62910 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T466 62950-62951 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T467 63418-63419 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T468 63760-63761 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T469 63815-63818 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T470 63854-63855 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T471 63987-63988 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T472 64048-64051 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T473 64085-64088 http://purl.obolibrary.org/obo/CLO_0001006 denotes 311
T474 64768-64771 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T475 64990-64991 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T476 65154-65155 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T477 65183-65184 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T478 65235-65240 http://purl.obolibrary.org/obo/CLO_0001236 denotes (2) a
T479 65292-65295 http://purl.obolibrary.org/obo/CLO_0001294 denotes 322
T480 65433-65434 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T481 65469-65472 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T482 65766-65769 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T483 66074-66075 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T484 66280-66281 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T485 66438-66439 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T486 67263-67264 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T487 67323-67324 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T488 67357-67358 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T489 67402-67408 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T490 67468-67469 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T491 67700-67706 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T492 67728-67734 http://purl.obolibrary.org/obo/UBERON_0000473 denotes tested
T493 67739-67745 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T494 67764-67769 http://purl.obolibrary.org/obo/CLO_0002932 denotes EOL-1
T495 67770-67775 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T496 67881-67887 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T497 67921-67929 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T498 67963-67969 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T499 68053-68054 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T500 68162-68170 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T501 68594-68596 http://purl.obolibrary.org/obo/CLO_0001022 denotes Li
T502 68594-68596 http://purl.obolibrary.org/obo/CLO_0007314 denotes Li
T503 68784-68787 http://purl.obolibrary.org/obo/PR_000017298 denotes VIM
T504 68983-68991 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T505 69464-69465 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T506 69763-69764 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T507 69841-69842 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T508 70165-70166 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T509 70492-70493 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T510 70618-70625 http://purl.obolibrary.org/obo/OBI_0100026 denotes organic
T511 70618-70625 http://purl.obolibrary.org/obo/UBERON_0000468 denotes organic
T512 70641-70642 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T513 70783-70784 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T514 71043-71044 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T515 71086-71087 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T516 71242-71243 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T517 71916-71917 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T518 72031-72032 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T519 72078-72079 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T520 72100-72101 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T521 72124-72125 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T522 72188-72189 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T523 72388-72389 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T524 72550-72551 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T525 72586-72587 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T526 72627-72628 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T527 72711-72712 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T528 72737-72738 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T529 73252-73258 http://purl.obolibrary.org/obo/CLO_0001658 denotes active
T530 73353-73354 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T531 73470-73473 http://purl.obolibrary.org/obo/CLO_0001310 denotes 351
T532 73782-73783 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T533 73968-73969 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T534 74185-74193 http://purl.obolibrary.org/obo/UBERON_0000158 denotes membrane
T535 74280-74281 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T536 74365-74373 http://purl.obolibrary.org/obo/UBERON_0000158 denotes membrane
T537 75137-75140 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T538 75209-75217 http://purl.obolibrary.org/obo/CHEBI_3815 denotes collagen
T539 75278-75281 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T540 75306-75311 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T541 75350-75351 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T542 75397-75398 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T543 75440-75448 http://purl.obolibrary.org/obo/UBERON_0000158 denotes membrane
T544 75511-75512 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T545 75636-75637 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T546 75659-75660 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T547 75689-75690 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T548 75857-75858 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T549 76072-76073 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T550 76105-76112 http://purl.obolibrary.org/obo/OBI_0100026 denotes organic
T551 76105-76112 http://purl.obolibrary.org/obo/UBERON_0000468 denotes organic
T552 76496-76497 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T553 76900-76901 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T554 76917-76920 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T555 76926-76927 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T556 77255-77256 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T557 77470-77472 http://purl.obolibrary.org/obo/PR_000005794 denotes CP
T558 77587-77588 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T559 77722-77731 http://purl.obolibrary.org/obo/UBERON_0000158 denotes membranes
T560 77736-77744 http://purl.obolibrary.org/obo/UBERON_0000158 denotes membrane
T561 77855-77863 http://purl.obolibrary.org/obo/UBERON_0000158 denotes membrane
T562 77909-77910 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T96610 77933-77935 http://purl.obolibrary.org/obo/PR_000005794 denotes CP
T564 78378-78379 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T565 78446-78454 http://purl.obolibrary.org/obo/PR_000018263 denotes peptides
T566 78524-78525 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T567 78619-78620 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T568 78655-78656 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T569 78965-78966 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T570 79037-79038 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T571 79059-79060 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T572 79092-79093 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T573 79125-79126 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T574 79244-79245 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T575 79354-79355 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T576 79432-79437 http://purl.obolibrary.org/obo/GO_0005623 denotes cells
T577 79442-79452 http://purl.obolibrary.org/obo/CLO_0000031 denotes cell lines
T578 79453-79463 http://purl.obolibrary.org/obo/CLO_0007634 denotes MDA-MB-231
T579 79453-79463 http://purl.obolibrary.org/obo/CLO_0037291 denotes MDA-MB-231
T580 79465-79471 http://purl.obolibrary.org/obo/UBERON_0000310 denotes breast
T581 79484-79488 http://purl.obolibrary.org/obo/CLO_0001601 denotes A549
T582 79484-79488 http://purl.obolibrary.org/obo/CLO_0050025 denotes A549
T583 79484-79488 http://purl.obolibrary.org/obo/CLO_0054264 denotes A549
T584 79484-79488 http://purl.obolibrary.org/obo/CLO_0054265 denotes A549
T585 79484-79488 http://purl.obolibrary.org/obo/CLO_0054266 denotes A549
T586 79484-79488 http://purl.obolibrary.org/obo/CLO_0054267 denotes A549
T587 79484-79488 http://purl.obolibrary.org/obo/CLO_0054268 denotes A549
T588 79484-79488 http://purl.obolibrary.org/obo/CLO_0054269 denotes A549
T589 79490-79494 http://purl.obolibrary.org/obo/UBERON_0002048 denotes lung
T590 79490-79494 http://www.ebi.ac.uk/efo/EFO_0000934 denotes lung
T591 79526-79527 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T592 79840-79844 http://purl.obolibrary.org/obo/GO_0005623 denotes cell
T593 79991-79992 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T594 80407-80414 http://purl.obolibrary.org/obo/PR_000018263 denotes peptide
T595 80744-80745 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T596 80746-80749 http://purl.obolibrary.org/obo/CLO_0053733 denotes 1:1
T597 80760-80767 http://purl.obolibrary.org/obo/PR_000018263 denotes peptide
T598 80991-80992 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T599 81060-81061 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T600 81071-81072 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T601 81098-81099 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T602 81147-81148 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T603 81224-81225 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T604 81281-81289 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T605 81432-81433 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T606 81591-81599 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T607 81693-81694 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T608 81842-81843 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T609 81906-81907 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T610 82287-82288 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T611 82323-82331 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T612 82364-82365 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T613 82723-82731 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T614 82797-82805 http://purl.obolibrary.org/obo/CLO_0001658 denotes activity
T615 82978-82979 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T616 83081-83084 http://purl.obolibrary.org/obo/CLO_0001319 denotes 372
T617 83125-83133 http://purl.obolibrary.org/obo/PR_000001898 denotes called A
T618 83298-83299 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T619 83300-83304 http://purl.obolibrary.org/obo/UBERON_0000473 denotes test
T620 83400-83405 http://purl.obolibrary.org/obo/NCBITaxon_9606 denotes human
T621 83528-83535 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeled
T622 83568-83575 http://purl.obolibrary.org/obo/UBERON_0000473 denotes testing
T623 83819-83823 http://purl.obolibrary.org/obo/UBERON_0000473 denotes test
T624 84211-84212 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T625 84308-84311 http://purl.obolibrary.org/obo/CLO_0001319 denotes 372
T626 84788-84791 http://purl.obolibrary.org/obo/CLO_0001007 denotes 380
T627 84962-84963 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T628 85003-85008 http://purl.obolibrary.org/obo/NCBITaxon_9606 denotes Human
T629 85026-85031 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T630 85934-85935 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T631 86072-86073 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T632 86341-86342 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T633 86376-86379 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T634 86565-86567 http://purl.obolibrary.org/obo/CLO_0053733 denotes 11
T635 87607-87608 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T636 87799-87800 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T637 87876-87877 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T638 87962-87963 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T639 88208-88209 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T640 88238-88245 http://purl.obolibrary.org/obo/PR_000018263 denotes peptide
T641 88310-88311 http://purl.obolibrary.org/obo/CLO_0001021 denotes B
T642 88452-88456 http://purl.obolibrary.org/obo/UBERON_0002535 denotes Gill
T643 89498-89499 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T644 89540-89541 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T645 89626-89627 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T646 89837-89840 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T647 89862-89867 http://purl.obolibrary.org/obo/UBERON_0007688 denotes field
T648 90697-90698 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T649 90707-90716 http://purl.obolibrary.org/obo/CLO_0001658 denotes activated
T650 90828-90830 http://purl.obolibrary.org/obo/CLO_0003599 denotes H4
T651 90832-90834 http://purl.obolibrary.org/obo/CLO_0003607 denotes H5
T652 90996-90997 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T653 91271-91272 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T654 91408-91409 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T655 91609-91610 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T656 91746-91747 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T657 91775-91781 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T658 92113-92114 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T659 92287-92289 http://purl.obolibrary.org/obo/CLO_0007874 denotes ms
T660 92378-92383 http://purl.obolibrary.org/obo/UBERON_0000948 denotes heart
T661 92378-92383 http://purl.obolibrary.org/obo/UBERON_0007100 denotes heart
T662 92378-92383 http://purl.obolibrary.org/obo/UBERON_0015228 denotes heart
T663 92378-92383 http://www.ebi.ac.uk/efo/EFO_0000815 denotes heart
T664 92530-92533 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T665 92582-92583 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T666 92666-92674 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T667 92815-92816 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T668 93103-93106 http://purl.obolibrary.org/obo/CLO_0051582 denotes has
T669 93354-93357 http://purl.obolibrary.org/obo/CLO_0037067 denotes Val
T670 93795-93796 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T671 93857-93866 http://purl.obolibrary.org/obo/CLO_0007225 denotes Labelling
T672 93867-93868 http://purl.obolibrary.org/obo/CLO_0001020 denotes A
T673 93974-93982 http://purl.obolibrary.org/obo/CLO_0007225 denotes labeling
T674 94012-94013 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T675 94317-94323 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T676 94340-94346 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T677 94454-94471 http://purl.obolibrary.org/obo/GO_0043234 denotes protein complexes
T678 94771-94777 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T679 94950-94951 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T680 95051-95056 http://purl.obolibrary.org/obo/NCBITaxon_10239 denotes virus
T681 95148-95149 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T682 95626-95632 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T683 95673-95679 http://purl.obolibrary.org/obo/SO_0000418 denotes signal
T684 96249-96250 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T685 96483-96484 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T686 96555-96556 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T687 97255-97256 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T688 97377-97378 http://purl.obolibrary.org/obo/CLO_0001020 denotes a
T689 97508-97509 http://purl.obolibrary.org/obo/CLO_0001020 denotes a

LitCovid-PD-CHEBI

Id Subject Object Predicate Lexical cue chebi_id
T12 270-274 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T13 316-330 Chemical denotes pharmaceutical http://purl.obolibrary.org/obo/CHEBI_52217
T14 387-392 Chemical denotes drugs http://purl.obolibrary.org/obo/CHEBI_23888
T15 465-469 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T16 547-551 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T17 777-781 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T18 970-974 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T19 1228-1233 Chemical denotes drugs http://purl.obolibrary.org/obo/CHEBI_23888
T20 2021-2030 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T21 2583-2592 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T22 2888-2892 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T23 2981-2987 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T24 3049-3056 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T25 3247-3251 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T26 3370-3374 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T27 3453-3457 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T28 3497-3505 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T29 3723-3727 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T30 3728-3735 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T31 3794-3798 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T32 3841-3845 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T33 3972-3976 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T34 4223-4237 Chemical denotes pharmaceutical http://purl.obolibrary.org/obo/CHEBI_52217
T35 4651-4660 Chemical denotes inhibitor http://purl.obolibrary.org/obo/CHEBI_35222
T36 4736-4749 Chemical denotes aspartic acid http://purl.obolibrary.org/obo/CHEBI_22660
T37 4745-4749 Chemical denotes acid http://purl.obolibrary.org/obo/CHEBI_37527
T38 4800-4812 Chemical denotes amyloid beta http://purl.obolibrary.org/obo/CHEBI_64645
T39 4808-4812 Chemical denotes beta http://purl.obolibrary.org/obo/CHEBI_10545
T40 4813-4821 Chemical denotes peptides http://purl.obolibrary.org/obo/CHEBI_16670
T41 5068-5074 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T42 5240-5250 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T43 5557-5565 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T44 5730-5732 Chemical denotes ID http://purl.obolibrary.org/obo/CHEBI_141439
T45 5855-5859 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T46 5928-5932 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
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T137 15430-15437 Chemical denotes glucose http://purl.obolibrary.org/obo/CHEBI_17234|http://purl.obolibrary.org/obo/CHEBI_4167
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T142 15473-15483 Chemical denotes synephrine http://purl.obolibrary.org/obo/CHEBI_29081|http://purl.obolibrary.org/obo/CHEBI_58606
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T145 15782-15784 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
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T93881 80509-80512 Chemical denotes Zn2 http://purl.obolibrary.org/obo/CHEBI_37256
T21514 80520-80523 Chemical denotes HHQ http://purl.obolibrary.org/obo/CHEBI_75306
T81340 80633-80636 Chemical denotes Zn2 http://purl.obolibrary.org/obo/CHEBI_37256
T13193 80702-80705 Chemical denotes Zn2 http://purl.obolibrary.org/obo/CHEBI_37256
T72066 80730-80733 Chemical denotes Zn2 http://purl.obolibrary.org/obo/CHEBI_37256
T34901 80756-80759 Chemical denotes ion http://purl.obolibrary.org/obo/CHEBI_24870
T47363 80760-80767 Chemical denotes peptide http://purl.obolibrary.org/obo/CHEBI_16670
T21736 80858-80866 Chemical denotes zinc ion http://purl.obolibrary.org/obo/CHEBI_27365
T1487 80858-80862 Chemical denotes zinc http://purl.obolibrary.org/obo/CHEBI_27363|http://purl.obolibrary.org/obo/CHEBI_30185
T21535 80863-80866 Chemical denotes ion http://purl.obolibrary.org/obo/CHEBI_24870
T390 80892-80901 Chemical denotes histidine http://purl.obolibrary.org/obo/CHEBI_27570
T68900 80973-80976 Chemical denotes Zn2 http://purl.obolibrary.org/obo/CHEBI_37256
T5849 80978-80982 Chemical denotes ions http://purl.obolibrary.org/obo/CHEBI_24870
T62464 81073-81081 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T30980 81542-81550 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T13331 81664-81668 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T9620 81761-81766 Chemical denotes drugs http://purl.obolibrary.org/obo/CHEBI_23888
T33030 81792-81800 Chemical denotes solution http://purl.obolibrary.org/obo/CHEBI_75958
T2096 81845-81849 Chemical denotes gold http://purl.obolibrary.org/obo/CHEBI_29287|http://purl.obolibrary.org/obo/CHEBI_30050
T91775 81873-81877 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T59537 81926-81930 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T77020 82020-82024 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T83203 82030-82040 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T23728 82078-82081 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T91597 82132-82143 Chemical denotes L-aspartate http://purl.obolibrary.org/obo/CHEBI_29991|http://purl.obolibrary.org/obo/CHEBI_29993
T69299 82134-82143 Chemical denotes aspartate http://purl.obolibrary.org/obo/CHEBI_132943|http://purl.obolibrary.org/obo/CHEBI_29995|http://purl.obolibrary.org/obo/CHEBI_72314
T96973 82167-82174 Chemical denotes alanine http://purl.obolibrary.org/obo/CHEBI_16449
T33547 82179-82193 Chemical denotes carbon dioxide http://purl.obolibrary.org/obo/CHEBI_16526
T30476 82179-82185 Chemical denotes carbon http://purl.obolibrary.org/obo/CHEBI_27594|http://purl.obolibrary.org/obo/CHEBI_33415
T5496 82254-82264 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T92820 82268-82271 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T41804 82335-82338 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T91787 82357-82360 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T96763 82366-82374 Chemical denotes solution http://purl.obolibrary.org/obo/CHEBI_75958
T44515 82378-82389 Chemical denotes L-aspartate http://purl.obolibrary.org/obo/CHEBI_29991|http://purl.obolibrary.org/obo/CHEBI_29993
T97142 82380-82389 Chemical denotes aspartate http://purl.obolibrary.org/obo/CHEBI_132943|http://purl.obolibrary.org/obo/CHEBI_29995|http://purl.obolibrary.org/obo/CHEBI_72314
T6242 82391-82402 Chemical denotes L-aspartate http://purl.obolibrary.org/obo/CHEBI_29991|http://purl.obolibrary.org/obo/CHEBI_29993
T69446 82393-82402 Chemical denotes aspartate http://purl.obolibrary.org/obo/CHEBI_132943|http://purl.obolibrary.org/obo/CHEBI_29995|http://purl.obolibrary.org/obo/CHEBI_72314
T40549 82433-82436 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T435 82454-82465 Chemical denotes L-aspartate http://purl.obolibrary.org/obo/CHEBI_29991|http://purl.obolibrary.org/obo/CHEBI_29993
T41649 82456-82465 Chemical denotes aspartate http://purl.obolibrary.org/obo/CHEBI_132943|http://purl.obolibrary.org/obo/CHEBI_29995|http://purl.obolibrary.org/obo/CHEBI_72314
T440 82471-82478 Chemical denotes alanine http://purl.obolibrary.org/obo/CHEBI_16449
T69358 82512-82523 Chemical denotes L-aspartate http://purl.obolibrary.org/obo/CHEBI_29991|http://purl.obolibrary.org/obo/CHEBI_29993
T70918 82514-82523 Chemical denotes aspartate http://purl.obolibrary.org/obo/CHEBI_132943|http://purl.obolibrary.org/obo/CHEBI_29995|http://purl.obolibrary.org/obo/CHEBI_72314
T65900 82563-82570 Chemical denotes alanine http://purl.obolibrary.org/obo/CHEBI_16449
T65308 82600-82603 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T75103 82608-82617 Chemical denotes inhibitor http://purl.obolibrary.org/obo/CHEBI_35222
T9845 82618-82622 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T10921 82709-82712 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T60253 82837-82847 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T31433 82851-82854 Chemical denotes ADC http://purl.obolibrary.org/obo/CHEBI_18198|http://purl.obolibrary.org/obo/CHEBI_35181
T18141 82941-82946 Chemical denotes drugs http://purl.obolibrary.org/obo/CHEBI_23888
T21665 82959-82964 Chemical denotes drugs http://purl.obolibrary.org/obo/CHEBI_23888
T95003 83134-83136 Chemical denotes La http://purl.obolibrary.org/obo/CHEBI_33336
T87043 83317-83324 Chemical denotes mixture http://purl.obolibrary.org/obo/CHEBI_60004
T15847 83351-83354 Chemical denotes DTT http://purl.obolibrary.org/obo/CHEBI_18320
T34147 83406-83408 Chemical denotes La http://purl.obolibrary.org/obo/CHEBI_33336
T40887 83409-83416 Chemical denotes antigen http://purl.obolibrary.org/obo/CHEBI_59132
T98818 83536-83538 Chemical denotes La http://purl.obolibrary.org/obo/CHEBI_33336
T99168 83539-83546 Chemical denotes antigen http://purl.obolibrary.org/obo/CHEBI_59132
T86355 83556-83563 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T82641 83595-83597 Chemical denotes La http://purl.obolibrary.org/obo/CHEBI_33336
T56507 83598-83605 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T98917 83824-83833 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T43119 83858-83868 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T59928 83872-83879 Chemical denotes histone http://purl.obolibrary.org/obo/CHEBI_15358
T28691 83904-83914 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T34467 84014-84028 Chemical denotes HAT inhibitors http://purl.obolibrary.org/obo/CHEBI_76395
T53938 84018-84028 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T44175 84534-84538 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T21417 84567-84571 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T76860 84939-84943 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T477 84974-84988 Chemical denotes benzodiazepine http://purl.obolibrary.org/obo/CHEBI_22720
T478 84989-84999 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T479 85237-85251 Chemical denotes benzodiazepine http://purl.obolibrary.org/obo/CHEBI_22720
T480 85252-85262 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T481 85321-85331 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T482 85450-85464 Chemical denotes benzodiazepine http://purl.obolibrary.org/obo/CHEBI_22720
T483 85465-85475 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T484 85490-85501 Chemical denotes amino acids http://purl.obolibrary.org/obo/CHEBI_33709
T485 85490-85495 Chemical denotes amino http://purl.obolibrary.org/obo/CHEBI_46882
T486 85496-85501 Chemical denotes acids http://purl.obolibrary.org/obo/CHEBI_37527
T487 85533-85547 Chemical denotes benzodiazepine http://purl.obolibrary.org/obo/CHEBI_22720
T488 85548-85558 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T489 85615-85617 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T490 85715-85729 Chemical denotes benzodiazepine http://purl.obolibrary.org/obo/CHEBI_22720
T491 85730-85740 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T492 85831-85845 Chemical denotes benzodiazepine http://purl.obolibrary.org/obo/CHEBI_22720
T493 85846-85856 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T494 86104-86111 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T495 86112-86119 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T496 86313-86321 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T497 86343-86350 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T498 86351-86358 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T499 86519-86527 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T500 86868-86870 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T501 87018-87020 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T502 87233-87235 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T503 87341-87350 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T504 87363-87370 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T505 87575-87582 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T506 87618-87622 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T507 87862-87872 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T508 87878-87885 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T509 87886-87893 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T510 87974-87978 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T511 88033-88041 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T512 88075-88080 Chemical denotes alpha http://purl.obolibrary.org/obo/CHEBI_30216
T513 88153-88163 Chemical denotes inhibitors http://purl.obolibrary.org/obo/CHEBI_35222
T514 88238-88245 Chemical denotes peptide http://purl.obolibrary.org/obo/CHEBI_16670
T515 88514-88518 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T516 88542-88546 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T517 88618-88626 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T518 88869-88878 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T519 89028-89035 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T520 89070-89079 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T521 89207-89215 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T522 89524-89528 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T523 89542-89549 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T524 89550-89557 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T525 89666-89670 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T526 89948-89952 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T527 90392-90398 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T528 90467-90474 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T529 90562-90569 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T530 90699-90706 Chemical denotes mitogen http://purl.obolibrary.org/obo/CHEBI_52290
T531 90717-90724 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T532 90741-90750 Chemical denotes inhibitor http://purl.obolibrary.org/obo/CHEBI_35222
T533 90751-90759 Chemical denotes SB203580 http://purl.obolibrary.org/obo/CHEBI_90705
T534 90846-90854 Chemical denotes SB203580 http://purl.obolibrary.org/obo/CHEBI_90705
T535 90930-90932 Chemical denotes H2 http://purl.obolibrary.org/obo/CHEBI_18276
T536 90942-90948 Chemical denotes methyl http://purl.obolibrary.org/obo/CHEBI_32875|http://purl.obolibrary.org/obo/CHEBI_29309
T538 90998-91011 Chemical denotes pyridine ring http://purl.obolibrary.org/obo/CHEBI_52884
T539 90998-91006 Chemical denotes pyridine http://purl.obolibrary.org/obo/CHEBI_16227
T540 91038-91046 Chemical denotes SB203580 http://purl.obolibrary.org/obo/CHEBI_90705
T541 91117-91123 Chemical denotes proton http://purl.obolibrary.org/obo/CHEBI_24636
T542 91153-91159 Chemical denotes proton http://purl.obolibrary.org/obo/CHEBI_24636
T543 91195-91203 Chemical denotes SB203580 http://purl.obolibrary.org/obo/CHEBI_90705
T544 91290-91297 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T545 91298-91304 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T546 91479-91485 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T547 91560-91567 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T548 91611-91618 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T549 91648-91655 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T550 91757-91763 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T551 91764-91770 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T552 91803-91810 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T553 91857-91864 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T554 91986-91992 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T555 92118-92125 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T556 92156-92164 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T557 92336-92345 Chemical denotes glycolate http://purl.obolibrary.org/obo/CHEBI_29805
T558 92346-92349 Chemical denotes NAD http://purl.obolibrary.org/obo/CHEBI_13389|http://purl.obolibrary.org/obo/CHEBI_15846
T560 92413-92420 Chemical denotes glucose http://purl.obolibrary.org/obo/CHEBI_17234|http://purl.obolibrary.org/obo/CHEBI_4167
T562 92423-92432 Chemical denotes phosphate http://purl.obolibrary.org/obo/CHEBI_18367|http://purl.obolibrary.org/obo/CHEBI_26020|http://purl.obolibrary.org/obo/CHEBI_35780|http://purl.obolibrary.org/obo/CHEBI_43474
T566 92433-92438 Chemical denotes NADPH http://purl.obolibrary.org/obo/CHEBI_16474|http://purl.obolibrary.org/obo/CHEBI_57783
T17092 92475-92482 Chemical denotes glucose http://purl.obolibrary.org/obo/CHEBI_17234|http://purl.obolibrary.org/obo/CHEBI_4167
T570 92725-92731 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T571 92757-92764 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T572 92834-92844 Chemical denotes amino acid http://purl.obolibrary.org/obo/CHEBI_33709
T573 92834-92839 Chemical denotes amino http://purl.obolibrary.org/obo/CHEBI_46882
T574 92840-92844 Chemical denotes acid http://purl.obolibrary.org/obo/CHEBI_37527
T575 92914-92920 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T576 92929-92939 Chemical denotes amino acid http://purl.obolibrary.org/obo/CHEBI_33709
T577 92929-92934 Chemical denotes amino http://purl.obolibrary.org/obo/CHEBI_46882
T578 92935-92939 Chemical denotes acid http://purl.obolibrary.org/obo/CHEBI_37527
T579 93015-93022 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T580 93065-93072 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T581 93073-93079 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T582 93178-93191 Chemical denotes benzimidazole http://purl.obolibrary.org/obo/CHEBI_36622|http://purl.obolibrary.org/obo/CHEBI_41275
T584 93214-93221 Chemical denotes uridine http://purl.obolibrary.org/obo/CHEBI_16704
T585 93254-93264 Chemical denotes UDP-GlcNAc http://purl.obolibrary.org/obo/CHEBI_16264
T586 93254-93257 Chemical denotes UDP http://purl.obolibrary.org/obo/CHEBI_17659|http://purl.obolibrary.org/obo/CHEBI_58223
T588 93258-93264 Chemical denotes GlcNAc http://purl.obolibrary.org/obo/CHEBI_506227|http://purl.obolibrary.org/obo/CHEBI_73685
T590 93330-93341 Chemical denotes amino acids http://purl.obolibrary.org/obo/CHEBI_33709
T591 93330-93335 Chemical denotes amino http://purl.obolibrary.org/obo/CHEBI_46882
T592 93336-93341 Chemical denotes acids http://purl.obolibrary.org/obo/CHEBI_37527
T593 93349-93352 Chemical denotes Ile http://purl.obolibrary.org/obo/CHEBI_17191|http://purl.obolibrary.org/obo/CHEBI_30009
T595 93354-93357 Chemical denotes Val http://purl.obolibrary.org/obo/CHEBI_16414|http://purl.obolibrary.org/obo/CHEBI_30015
T597 93359-93362 Chemical denotes Leu http://purl.obolibrary.org/obo/CHEBI_15603|http://purl.obolibrary.org/obo/CHEBI_25017|http://purl.obolibrary.org/obo/CHEBI_30006
T600 93364-93367 Chemical denotes Met http://purl.obolibrary.org/obo/CHEBI_16044|http://purl.obolibrary.org/obo/CHEBI_16643|http://purl.obolibrary.org/obo/CHEBI_16811
T603 93375-93378 Chemical denotes Trp http://purl.obolibrary.org/obo/CHEBI_16828|http://purl.obolibrary.org/obo/CHEBI_27897|http://purl.obolibrary.org/obo/CHEBI_29954
T606 93380-93383 Chemical denotes Phe http://purl.obolibrary.org/obo/CHEBI_17295|http://purl.obolibrary.org/obo/CHEBI_29997
T608 93473-93479 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T609 93526-93537 Chemical denotes amino acids http://purl.obolibrary.org/obo/CHEBI_33709
T610 93526-93531 Chemical denotes amino http://purl.obolibrary.org/obo/CHEBI_46882
T611 93532-93537 Chemical denotes acids http://purl.obolibrary.org/obo/CHEBI_37527
T612 93583-93589 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T613 93680-93684 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T614 93851-93856 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T615 93991-93996 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T616 94014-94030 Chemical denotes tert-butyl group http://purl.obolibrary.org/obo/CHEBI_30355
T617 94019-94024 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T618 94025-94030 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T619 94048-94054 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T620 94100-94107 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T621 94108-94114 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T622 94134-94150 Chemical denotes tert-butyl group http://purl.obolibrary.org/obo/CHEBI_30355
T623 94139-94144 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T624 94145-94150 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T625 94217-94223 Chemical denotes methyl http://purl.obolibrary.org/obo/CHEBI_32875|http://purl.obolibrary.org/obo/CHEBI_29309
T627 94237-94243 Chemical denotes methyl http://purl.obolibrary.org/obo/CHEBI_32875|http://purl.obolibrary.org/obo/CHEBI_29309
T629 94270-94275 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T630 94310-94312 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T631 94329-94339 Chemical denotes tert-butyl http://purl.obolibrary.org/obo/CHEBI_30355
T632 94334-94339 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T633 94454-94461 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T634 94579-94595 Chemical denotes tert-butyl group http://purl.obolibrary.org/obo/CHEBI_30355
T635 94584-94589 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T636 94590-94595 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T637 94709-94717 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T638 94814-94830 Chemical denotes tert-butyl group http://purl.obolibrary.org/obo/CHEBI_30355
T639 94819-94824 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T640 94825-94830 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T641 94938-94945 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T642 94989-94995 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T643 95003-95010 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T644 95130-95136 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T645 95150-95166 Chemical denotes tert-butyl group http://purl.obolibrary.org/obo/CHEBI_30355
T646 95155-95160 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T647 95161-95166 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T648 95222-95238 Chemical denotes tert-butyl group http://purl.obolibrary.org/obo/CHEBI_30355
T649 95227-95232 Chemical denotes butyl http://purl.obolibrary.org/obo/CHEBI_41264
T650 95233-95238 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T651 95242-95248 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T652 95327-95333 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T653 95358-95364 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T654 95523-95528 Chemical denotes probe http://purl.obolibrary.org/obo/CHEBI_50406
T655 95533-95540 Chemical denotes solvent http://purl.obolibrary.org/obo/CHEBI_46787
T656 95562-95568 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T657 95606-95612 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T658 95693-95699 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T659 95717-95724 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T660 95731-95738 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T661 95800-95807 Chemical denotes prodrug http://purl.obolibrary.org/obo/CHEBI_50266
T662 95893-95900 Chemical denotes quinone http://purl.obolibrary.org/obo/CHEBI_36141
T663 96215-96225 Chemical denotes asparagine http://purl.obolibrary.org/obo/CHEBI_22653
T664 96251-96259 Chemical denotes hydrogen http://purl.obolibrary.org/obo/CHEBI_49637
T665 96311-96320 Chemical denotes aziridine http://purl.obolibrary.org/obo/CHEBI_30969
T666 96361-96368 Chemical denotes solvent http://purl.obolibrary.org/obo/CHEBI_46787
T23797 96496-96503 Chemical denotes solvent http://purl.obolibrary.org/obo/CHEBI_46787
T25837 96578-96585 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T75648 96661-96667 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T96730 96707-96714 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T53890 96794-96801 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T32855 96842-96849 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T55729 96891-96898 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T47776 96937-96955 Chemical denotes triazolopyridazine http://purl.obolibrary.org/obo/CHEBI_48384
T84009 96971-96978 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T62193 97089-97095 Chemical denotes methyl http://purl.obolibrary.org/obo/CHEBI_32875|http://purl.obolibrary.org/obo/CHEBI_29309
T44312 97096-97101 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T25777 97107-97113 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T26250 97126-97132 Chemical denotes proton http://purl.obolibrary.org/obo/CHEBI_24636
T88957 97138-97144 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T85582 97160-97166 Chemical denotes proton http://purl.obolibrary.org/obo/CHEBI_24636
T46490 97172-97178 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T38398 97196-97201 Chemical denotes water http://purl.obolibrary.org/obo/CHEBI_15377
T94756 97305-97310 Chemical denotes water http://purl.obolibrary.org/obo/CHEBI_15377
T55063 97311-97320 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T3389 97365-97371 Chemical denotes proton http://purl.obolibrary.org/obo/CHEBI_24636
T5082 97389-97396 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T39367 97412-97430 Chemical denotes triazolopyridazine http://purl.obolibrary.org/obo/CHEBI_48384
T28009 97473-97478 Chemical denotes amino http://purl.obolibrary.org/obo/CHEBI_46882
T17318 97548-97555 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T1462 97637-97644 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T73744 97709-97727 Chemical denotes triazolopyridazine http://purl.obolibrary.org/obo/CHEBI_48384
T45570 97736-97742 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T6158 97751-97763 Chemical denotes methyl group http://purl.obolibrary.org/obo/CHEBI_32875
T85158 97751-97757 Chemical denotes methyl http://purl.obolibrary.org/obo/CHEBI_29309
T13480 97758-97763 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T97666 97805-97810 Chemical denotes amino http://purl.obolibrary.org/obo/CHEBI_46882
T70994 97811-97816 Chemical denotes group http://purl.obolibrary.org/obo/CHEBI_24433
T86094 97837-97845 Chemical denotes hydrogen http://purl.obolibrary.org/obo/CHEBI_49637
T60748 98089-98097 Chemical denotes solution http://purl.obolibrary.org/obo/CHEBI_75958
T70776 98311-98318 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T46909 98429-98436 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T58074 98440-98446 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T32483 98540-98546 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T32375 98572-98574 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T80174 98587-98589 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T35438 98631-98637 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T25554 98649-98655 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T34470 98656-98663 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T57878 98747-98749 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T38614 98750-98752 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T60908 98890-98896 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T47768 98918-98925 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T66836 99016-99022 Chemical denotes methyl http://purl.obolibrary.org/obo/CHEBI_32875|http://purl.obolibrary.org/obo/CHEBI_29309
T46479 99035-99042 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T85952 99215-99222 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T21306 99351-99355 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T85693 99374-99376 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T57200 99501-99508 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T43008 99560-99567 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T28259 99637-99643 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T70946 99674-99681 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T39339 99743-99749 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T77983 99805-99812 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T24857 99833-99835 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T79343 99852-99859 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T60641 99931-99939 Chemical denotes hydrogen http://purl.obolibrary.org/obo/CHEBI_49637
T37117 100077-100093 Chemical denotes naphthoate ester http://purl.obolibrary.org/obo/CHEBI_46831
T41675 100077-100087 Chemical denotes naphthoate http://purl.obolibrary.org/obo/CHEBI_25482
T79793 100088-100093 Chemical denotes ester http://purl.obolibrary.org/obo/CHEBI_35701
T85096 100124-100134 Chemical denotes fatty acid http://purl.obolibrary.org/obo/CHEBI_35366
T48890 100130-100134 Chemical denotes acid http://purl.obolibrary.org/obo/CHEBI_37527
T92250 100143-100150 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T53375 100160-100169 Chemical denotes ketorolac http://purl.obolibrary.org/obo/CHEBI_6129
T64655 100170-100173 Chemical denotes ANS http://purl.obolibrary.org/obo/CHEBI_39708
T63906 100262-100268 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T65279 100305-100312 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T23599 100313-100319 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T79552 100465-100472 Chemical denotes Protein http://purl.obolibrary.org/obo/CHEBI_16541
T41635 100553-100561 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T4092 100614-100621 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T35786 100704-100711 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T89568 100992-100998 Chemical denotes serine http://purl.obolibrary.org/obo/CHEBI_17822
T81502 101028-101037 Chemical denotes inhibitor http://purl.obolibrary.org/obo/CHEBI_35222
T93491 101038-101060 Chemical denotes chymotrypsin inhibitor http://purl.obolibrary.org/obo/CHEBI_64943
T66488 101051-101060 Chemical denotes inhibitor http://purl.obolibrary.org/obo/CHEBI_35222
T88221 101121-101143 Chemical denotes chymotrypsin inhibitor http://purl.obolibrary.org/obo/CHEBI_64943
T34199 101134-101143 Chemical denotes inhibitor http://purl.obolibrary.org/obo/CHEBI_35222
T50928 101704-101712 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T73305 101718-101725 Chemical denotes ligands http://purl.obolibrary.org/obo/CHEBI_52214
T694 101733-101742 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T6431 101826-101830 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T12156 102126-102133 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T904 102675-102682 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T68030 102706-102714 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T15087 103187-103198 Chemical denotes application http://purl.obolibrary.org/obo/CHEBI_33232
T28739 103327-103335 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T30354 103390-103395 Chemical denotes probe http://purl.obolibrary.org/obo/CHEBI_50406
T31171 103400-103407 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T89156 103408-103414 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T4462 103502-103509 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T53184 103510-103516 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T12716 103591-103599 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T55010 103717-103724 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T36099 103802-103810 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T27611 103849-103852 Chemical denotes DNA http://purl.obolibrary.org/obo/CHEBI_16991
T26374 103870-103879 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T78103 104049-104055 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T8816 104134-104140 Chemical denotes ligand http://purl.obolibrary.org/obo/CHEBI_52214
T57310 104332-104339 Chemical denotes histone http://purl.obolibrary.org/obo/CHEBI_15358
T38623 104356-104362 Chemical denotes acetyl http://purl.obolibrary.org/obo/CHEBI_40574|http://purl.obolibrary.org/obo/CHEBI_46887
T69261 104407-104414 Chemical denotes peptide http://purl.obolibrary.org/obo/CHEBI_16670
T57840 104541-104546 Chemical denotes probe http://purl.obolibrary.org/obo/CHEBI_50406
T91758 104634-104642 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T76741 104735-104743 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T32116 104806-104814 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T22144 104844-104852 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T56756 105222-105229 Chemical denotes protein http://purl.obolibrary.org/obo/CHEBI_36080
T85962 105333-105347 Chemical denotes macromolecules http://purl.obolibrary.org/obo/CHEBI_33839
T98627 105557-105565 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T21932 105591-105599 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T71997 105696-105704 Chemical denotes proteins http://purl.obolibrary.org/obo/CHEBI_36080
T71491 105932-105946 Chemical denotes macromolecules http://purl.obolibrary.org/obo/CHEBI_33839
T9832 105998-106007 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T55558 106140-106149 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T52166 106169-106174 Chemical denotes probe http://purl.obolibrary.org/obo/CHEBI_50406
T58696 106325-106329 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T34375 106391-106399 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T83294 106782-106791 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T52890 106819-106821 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T99937 106869-106880 Chemical denotes metabolites http://purl.obolibrary.org/obo/CHEBI_25212
T24129 107013-107015 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T60832 107084-107093 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367
T95563 107111-107113 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T73804 107190-107192 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T85566 107193-107197 Chemical denotes atom http://purl.obolibrary.org/obo/CHEBI_33250
T17833 107262-107268 Chemical denotes nuclei http://purl.obolibrary.org/obo/CHEBI_33252
T65490 107276-107284 Chemical denotes molecule http://purl.obolibrary.org/obo/CHEBI_25367
T31918 107622-107626 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T99336 107903-107905 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T52045 108013-108019 Chemical denotes helium http://purl.obolibrary.org/obo/CHEBI_30217|http://purl.obolibrary.org/obo/CHEBI_33681
T12505 108792-108794 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T35513 108802-108804 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T63952 108879-108881 Chemical denotes 1H http://purl.obolibrary.org/obo/CHEBI_49637
T89677 108944-108950 Chemical denotes nuclei http://purl.obolibrary.org/obo/CHEBI_33252
T99623 109158-109162 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T80025 110456-110459 Chemical denotes MDD http://purl.obolibrary.org/obo/CHEBI_566274
T23405 110715-110717 Chemical denotes CS http://purl.obolibrary.org/obo/CHEBI_73462
T45982 111085-111091 Chemical denotes nuclei http://purl.obolibrary.org/obo/CHEBI_33252
T35824 111245-111256 Chemical denotes application http://purl.obolibrary.org/obo/CHEBI_33232
T70136 111988-111992 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T45865 112913-112919 Chemical denotes nuclei http://purl.obolibrary.org/obo/CHEBI_33252
T41882 112975-112978 Chemical denotes DNP http://purl.obolibrary.org/obo/CHEBI_53018
T48051 113013-113018 Chemical denotes atoms http://purl.obolibrary.org/obo/CHEBI_33250
T81359 113266-113272 Chemical denotes nuclei http://purl.obolibrary.org/obo/CHEBI_33252
T38349 113314-113318 Chemical denotes gold http://purl.obolibrary.org/obo/CHEBI_29287|http://purl.obolibrary.org/obo/CHEBI_30050
T25174 113339-113343 Chemical denotes drug http://purl.obolibrary.org/obo/CHEBI_23888
T70916 113659-113668 Chemical denotes molecules http://purl.obolibrary.org/obo/CHEBI_25367

LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
18 108-111 Gene denotes Oct Gene:5362
19 749-753 Gene denotes high Gene:104137
20 31-41 Species denotes SARS-CoV-2 Tax:2697049
21 42-50 Disease denotes COVID-19 MESH:C000657245
25 1244-1251 Species denotes patient Tax:9606
26 1651-1659 Species denotes patients Tax:9606
27 1490-1509 Disease denotes learning algorithms MESH:D007859
31 2161-2165 Gene denotes high Gene:104137
32 1722-1726 Gene denotes high Gene:104137
33 3794-3807 Disease denotes drug toxicity MESH:D064420
44 4675-4681 Gene denotes BACE-1 Gene:23621
45 4706-4712 Gene denotes BACE-1 Gene:23621
46 4800-4812 Gene denotes amyloid beta Gene:351
47 4977-4983 Gene denotes BACE-1 Gene:23621
48 5233-5239 Gene denotes BACE-1 Gene:23621
49 4951-4962 Chemical denotes isothiourea MESH:D013890
50 5085-5096 Chemical denotes isothiourea MESH:D013890
51 5211-5229 Chemical denotes iminopyrimidinones
52 4685-4704 Disease denotes Alzheimer’s disease MESH:D000544
53 4863-4882 Disease denotes Alzheimer’s disease MESH:D000544
56 6758-6762 Gene denotes spin Gene:10927
57 6604-6608 Gene denotes spin Gene:10927
60 8301-8305 Gene denotes spin Gene:10927
64 9100-9104 Gene denotes high Gene:104137
65 8955-8958 Chemical denotes D2O
77 10490-10494 Gene denotes high Gene:104137
78 10280-10284 Gene denotes high Gene:104137
79 9923-9927 Gene denotes high Gene:104137
80 10407-10409 Chemical denotes 1H
81 10543-10551 Chemical denotes hydrogen MESH:D006859
82 10788-10790 Chemical denotes 1D
83 10791-10793 Chemical denotes 1H
84 10813-10816 Chemical denotes 13C MESH:C000615229
85 10825-10828 Chemical denotes 15N
86 10838-10840 Chemical denotes 1D
87 10841-10844 Chemical denotes 31P
89 10938-10943 Chemical denotes 1D 1H
115 12308-12312 Gene denotes spin Gene:10927
116 10952-10954 Chemical denotes 1H
117 10955-10963 Chemical denotes hydrogen MESH:D006859
118 11035-11042 Chemical denotes tritium MESH:D014316
119 11165-11167 Chemical denotes 1D
120 11168-11170 Chemical denotes 1H
121 11302-11304 Chemical denotes 1H
122 11518-11523 Chemical denotes water MESH:D014867
123 11725-11730 Chemical denotes water MESH:D014867
124 11783-11788 Chemical denotes water MESH:D014867
125 12158-12163 Chemical denotes water MESH:D014867
126 12188-12196 Chemical denotes hydrogen MESH:D006859
127 12202-12205 Chemical denotes H2O
128 12349-12354 Chemical denotes water MESH:D014867
129 12510-12515 Chemical denotes water MESH:D014867
130 12880-12885 Chemical denotes water MESH:D014867
131 12907-12912 Chemical denotes WATER MESH:D014867
132 13096-13101 Chemical denotes water MESH:D014867
133 13205-13210 Chemical denotes water MESH:D014867
134 13380-13385 Chemical denotes water MESH:D014867
135 13525-13530 Chemical denotes water MESH:D014867
136 13754-13756 Chemical denotes 1H
137 13883-13885 Chemical denotes 1H
138 13984-13987 Chemical denotes 13C MESH:C000615229
139 13989-13992 Chemical denotes 15N
141 14038-14044 Chemical denotes 1D 13C
167 14063-14065 Chemical denotes 1H
168 14067-14070 Chemical denotes 13C MESH:C000615229
169 14160-14163 Chemical denotes 13C MESH:C000615229
170 14240-14242 Chemical denotes 1H
171 14257-14260 Chemical denotes 13C MESH:C000615229
172 14692-14698 Chemical denotes carbon MESH:D002244
173 14820-14823 Chemical denotes 13C MESH:C000615229
174 14963-14965 Chemical denotes 1H
175 14970-14973 Chemical denotes 13C MESH:C000615229
176 15182-15184 Chemical denotes 1H
177 15192-15195 Chemical denotes 13C MESH:C000615229
178 15219-15221 Chemical denotes 1H
179 15281-15289 Chemical denotes naringin MESH:C005274
180 15291-15298 Chemical denotes sucrose MESH:D013395
181 15306-15313 Chemical denotes glucose MESH:D005947
182 15322-15325 Chemical denotes 13C MESH:C000615229
183 15396-15404 Chemical denotes naringin MESH:C005274
184 15406-15419 Chemical denotes neohesperidin MESH:C546526
185 15430-15437 Chemical denotes glucose MESH:D005947
186 15439-15446 Chemical denotes sucrose MESH:D013395
187 15448-15456 Chemical denotes limonene MESH:D000077222
188 15458-15467 Chemical denotes narirutin MESH:C500601
189 15473-15483 Chemical denotes synephrine MESH:D013578
190 15519-15522 Chemical denotes 13C MESH:C000615229
191 15625-15627 Chemical denotes 1H
193 15655-15661 Chemical denotes 1D 15N
206 16388-16392 Gene denotes a 2D Gene:11273
207 15705-15708 Chemical denotes 15N
208 15753-15756 Chemical denotes 13C MESH:C000615229
209 15782-15784 Chemical denotes 1H
210 15935-15937 Chemical denotes 1H
211 15955-15958 Chemical denotes 15N
212 16017-16019 Chemical denotes 1H
213 16057-16060 Chemical denotes 15N
214 16075-16077 Chemical denotes 1H
215 16175-16178 Chemical denotes 15N
216 16199-16202 Chemical denotes 13C MESH:C000615229
217 16334-16350 Chemical denotes 15N-ethanolamine
219 17122-17128 Chemical denotes 1D 31P
232 17890-17897 Species denotes E. coli Tax:562
233 18015-18022 Species denotes E. coli Tax:562
234 17223-17225 Chemical denotes 1H
235 17246-17256 Chemical denotes phosphorus MESH:D010758
236 17373-17376 Chemical denotes 31P
237 17467-17477 Chemical denotes phosphorus MESH:D010758
238 17494-17497 Chemical denotes 31P
239 17555-17567 Chemical denotes phospholipid MESH:D010743
240 17580-17583 Chemical denotes ATP MESH:D000255
241 17585-17589 Chemical denotes NADP MESH:D009249
242 18036-18046 Chemical denotes ampicillin MESH:D000667
243 18364-18374 Chemical denotes phosphorus MESH:D010758
251 18485-18488 Chemical denotes 13C MESH:C000615229
252 18493-18496 Chemical denotes 15N
253 18605-18649 Chemical denotes 2-chloro-4,4,5,5-tetramethyldioxaphospholane MESH:C548759
254 18651-18656 Chemical denotes CTMDP MESH:C548759
255 18682-18688 Chemical denotes lipids MESH:D008055
256 18710-18718 Chemical denotes aldehyde MESH:D000447
257 18724-18732 Chemical denotes carboxyl
261 19643-19648 Gene denotes 2.2.1 Gene:54097
262 19653-19655 Chemical denotes 1H
263 19656-19658 Chemical denotes 1H
282 21489-21493 Species denotes rats Tax:10116
283 21730-21734 Species denotes rats Tax:10116
284 19793-19795 Chemical denotes 1H
285 19796-19798 Chemical denotes 1H
286 20327-20329 Chemical denotes 1H
287 20334-20340 Chemical denotes carbon MESH:D002244
288 20357-20363 Chemical denotes carbon MESH:D002244
289 21614-21616 Chemical denotes 1H
290 21627-21629 Chemical denotes 1H
291 21646-21648 Chemical denotes 1H
292 21649-21651 Chemical denotes 1H
293 21662-21664 Chemical denotes 1H
294 21665-21668 Chemical denotes 13C MESH:C000615229
295 21857-21864 Chemical denotes lactate MESH:D019344
296 21866-21878 Chemical denotes nicotinamide MESH:D009536
297 21880-21888 Chemical denotes glycerol MESH:D005990
298 21893-21900 Chemical denotes formate MESH:C030544
299 21472-21488 Disease denotes blood deficiency MESH:D007022
302 22158-22160 Chemical denotes 1H
303 22161-22163 Chemical denotes 1H
337 23637-23641 Gene denotes spin Gene:10927
338 23599-23603 Gene denotes spin Gene:10927
339 22934-22938 Gene denotes spin Gene:10927
340 22551-22555 Gene denotes spin Gene:10927
341 24152-24160 Species denotes patients Tax:9606
342 24330-24338 Species denotes patients Tax:9606
343 24600-24608 Species denotes patients Tax:9606
344 24964-24972 Species denotes patients Tax:9606
345 25139-25147 Species denotes patients Tax:9606
346 22325-22327 Chemical denotes 1H
347 22328-22330 Chemical denotes 1H
348 24107-24118 Chemical denotes gemcitabine MESH:C056507
349 24119-24130 Chemical denotes carboplatin MESH:D016190
350 24132-24134 Chemical denotes GC
351 24242-24256 Chemical denotes anthracyclines MESH:D018943
352 24261-24268 Chemical denotes taxanes MESH:D043823
353 24385-24387 Chemical denotes 1H
354 24453-24455 Chemical denotes 1H
355 24456-24458 Chemical denotes 1H
356 24467-24469 Chemical denotes 1H
357 24477-24479 Chemical denotes 1H
358 24480-24483 Chemical denotes 13C MESH:C000615229
359 24494-24496 Chemical denotes 1H
360 24497-24500 Chemical denotes 13C MESH:C000615229
361 24575-24586 Chemical denotes gemcitabine MESH:C056507
362 24587-24598 Chemical denotes carboplatin MESH:D016190
363 24939-24946 Chemical denotes acetate MESH:D000085
364 22265-22271 Disease denotes HOHAHA
365 24177-24190 Disease denotes breast cancer MESH:D001943
366 24753-24755 Disease denotes SD MESH:D029461
367 24761-24780 Disease denotes progressive disease MESH:D018450
368 24782-24784 Disease denotes PD MESH:D010300
369 24950-24963 Disease denotes breast cancer MESH:D001943
372 25223-25225 Chemical denotes 1H
373 25226-25229 Chemical denotes 13C MESH:C000615229
391 25370-25373 Chemical denotes 13C MESH:C000615229
392 25438-25441 Chemical denotes 13C MESH:C000615229
393 25545-25547 Chemical denotes 1H
394 25548-25551 Chemical denotes 13C MESH:C000615229
395 25555-25557 Chemical denotes 1H
396 25558-25561 Chemical denotes 15N
397 25719-25721 Chemical denotes 1H
398 25722-25725 Chemical denotes 13C MESH:C000615229
399 25726-25729 Chemical denotes 15N
400 25816-25818 Chemical denotes 1H
401 25853-25856 Chemical denotes 13C MESH:C000615229
402 25857-25860 Chemical denotes 15N
403 26002-26008 Chemical denotes carbon MESH:D002244
404 26047-26050 Chemical denotes 13C MESH:C000615229
405 26111-26113 Chemical denotes 1H
406 26117-26120 Chemical denotes 13C MESH:C000615229
407 26184-26187 Chemical denotes 13C MESH:C000615229
425 26622-26627 Species denotes Human Tax:9606
426 26294-26303 Chemical denotes cisplatin MESH:D002945
427 26498-26504 Chemical denotes Ptac2S
428 26531-26533 Chemical denotes 1H
429 26534-26537 Chemical denotes 13C MESH:C000615229
430 26554-26556 Chemical denotes 1H
431 26685-26690 Chemical denotes lipid MESH:D008055
432 26776-26782 Chemical denotes Ptac2S
433 26797-26805 Chemical denotes pyruvate MESH:D019289
434 26837-26846 Chemical denotes cisplatin MESH:D002945
435 26901-26906 Chemical denotes lipid MESH:D008055
436 26967-26973 Chemical denotes Ptac2S
437 26997-27006 Chemical denotes cisplatin MESH:D002945
438 27061-27067 Chemical denotes Ptac2S
439 27088-27097 Chemical denotes cisplatin MESH:D002945
440 26274-26286 Disease denotes cytotoxicity MESH:D064420
441 26314-26342 Disease denotes epithelial ovarian carcinoma MESH:D010051
444 27143-27145 Chemical denotes 1H
445 27147-27150 Chemical denotes 13C MESH:C000615229
449 27256-27258 Chemical denotes 1H
450 27292-27295 Chemical denotes 13C MESH:C000615229
451 27617-27619 Chemical denotes 1H
467 29028-29032 Gene denotes pill Gene:8319132
468 28449-28453 Gene denotes high Gene:104137
469 28165-28169 Species denotes rats Tax:10116
470 28282-28286 Species denotes rats Tax:10116
471 28571-28574 Species denotes rat Tax:10116
472 28225-28229 Gene denotes pill Gene:8319132
473 28791-28793 Chemical denotes 1H
474 28902-28904 Chemical denotes 1H
475 28905-28907 Chemical denotes 1H
476 28914-28916 Chemical denotes 1H
477 28917-28920 Chemical denotes 13C MESH:C000615229
478 28931-28933 Chemical denotes 1H
479 28934-28937 Chemical denotes 13C MESH:C000615229
480 29167-29172 Chemical denotes lipid MESH:D008055
481 28466-28468 Disease denotes HD MESH:D006816
485 30138-30142 Gene denotes spin Gene:10927
486 30133-30137 Gene denotes spin Gene:10927
487 29965-29969 Gene denotes spin Gene:10927
495 31843-31845 Chemical denotes 1D
496 31850-31852 Chemical denotes 2D
497 31935-31937 Chemical denotes 1D
498 32009-32014 Chemical denotes FK506 MESH:D016559
499 32130-32132 Chemical denotes 1H
500 32399-32402 Chemical denotes 15N
501 32458-32461 Chemical denotes 15N
503 32580-32584 Gene denotes Carr Gene:407
508 33291-33295 Gene denotes Carr Gene:407
509 32794-32798 Gene denotes spin Gene:10927
510 33497-33500 Chemical denotes 13C MESH:C000615229
511 33545-33548 Chemical denotes 13C MESH:C000615229
514 34490-34494 Gene denotes spin Gene:10927
515 34485-34489 Gene denotes spin Gene:10927
518 36073-36077 Gene denotes high Gene:104137
519 35409-35412 Chemical denotes 15N
521 36778-36781 Species denotes SAR Tax:2698737
526 37851-37855 Gene denotes High Gene:104137
527 37578-37582 Chemical denotes FBDD
528 37698-37702 Chemical denotes FBDD
529 38407-38411 Chemical denotes FBDD
542 39738-39742 Gene denotes BRAF Gene:673
543 40051-40055 Gene denotes CDK4 Gene:1019
544 39824-39832 Species denotes patients Tax:9606
545 39905-39913 Species denotes patients Tax:9606
546 39658-39669 Chemical denotes vemurafenib MESH:D000077484
547 39677-39688 Chemical denotes Vemurafenib MESH:D000077484
548 39865-39875 Chemical denotes Venetoclax MESH:C579720
549 40012-40016 Chemical denotes FBDD
550 40152-40163 Chemical denotes vemurafenib MESH:D000077484
551 39750-39756 Disease denotes cancer MESH:D009369
552 39849-39857 Disease denotes melanoma MESH:D008545
553 39919-39947 Disease denotes chronic lymphocytic leukemia MESH:D015451
559 40560-40563 Species denotes SAR Tax:2698737
560 40652-40655 Species denotes SAR Tax:2698737
561 40867-40869 Chemical denotes 1H
562 40870-40873 Chemical denotes 15N
563 41248-41265 Chemical denotes 2-phenylimidazole MESH:C059194
566 41821-41824 Species denotes SAR Tax:2698737
567 41589-41593 Chemical denotes FBDD
574 42256-42260 Gene denotes High Gene:104137
575 41912-41915 Species denotes SAR Tax:2698737
576 42203-42206 Species denotes SAR Tax:2698737
577 42290-42293 Species denotes SAR Tax:2698737
578 42489-42492 Species denotes SAR Tax:2698737
579 42777-42780 Species denotes SAR Tax:2698737
582 43302-43305 Chemical denotes 13C MESH:C000615229
583 43310-43313 Chemical denotes 15N
586 44917-44922 Chemical denotes Water MESH:D014867
587 45071-45076 Chemical denotes water MESH:D014867
591 46583-46599 Species denotes human rhinovirus Tax:169066
592 46612-46616 Species denotes HRV2 Tax:12130
593 46750-46754 Species denotes HRV2 Tax:12130
595 47950-47954 Gene denotes spin Gene:10927
597 48831-48835 Gene denotes high Gene:104137
606 50665-50669 Gene denotes HBGA Gene:3047
607 50599-50603 Gene denotes HBGA Gene:3047
608 49487-49492 Species denotes human Tax:9606
609 49856-49881 Chemical denotes A- and B-tetrasaccharides
610 50421-50426 Chemical denotes L-Fuc
611 50431-50446 Chemical denotes B-trisaccharide
612 49303-49318 Disease denotes gastroenteritis MESH:D005759
613 49577-49586 Disease denotes infection MESH:D007239
621 53872-53882 Gene denotes E-selectin Gene:6401
622 51712-51716 Gene denotes spin Gene:10927
623 51461-51465 Gene denotes spin Gene:10927
624 52840-52844 Gene denotes high Gene:104137
625 52716-52720 Gene denotes high Gene:104137
626 51935-51939 Gene denotes high Gene:104137
627 53810-53825 Chemical denotes polysaccharides MESH:D011134
631 56189-56193 Gene denotes spin Gene:10927
632 55032-55044 Chemical denotes baccatin III MESH:C073950
633 55049-55061 Chemical denotes epothilone A MESH:C093787
635 58950-58954 Gene denotes spin Gene:10927
640 62650-62655 Chemical denotes FK506 MESH:D016559
641 62830-62849 Chemical denotes p-ethoxyiodobenzene
642 62854-62881 Chemical denotes 2-iodo-6-methoxynaphthalene
643 62919-62936 Chemical denotes (4-hydroxyphenyl)
650 63050-63054 Gene denotes spin Gene:10927
651 63019-63021 Chemical denotes 1H
652 63109-63115 Chemical denotes Rf-PEG
653 63129-63143 Chemical denotes 5-fluorouracil MESH:D005472
654 63153-63180 Chemical denotes 1,3-dimethyl-5-fluorouracil
655 63182-63186 Chemical denotes DMFU
659 63730-63743 Gene denotes serum albumin Gene:213
660 63567-63571 Gene denotes high Gene:104137
661 63485-63505 Chemical denotes N-acetyl glucosamine MESH:D000117
663 64992-64996 Gene denotes high Gene:104137
666 66244-66253 Chemical denotes adenosine MESH:D000241
667 66315-66334 Disease denotes Parkinson’s disease MESH:D010300
679 67225-67254 Gene denotes ubiquitin specific protease 7 Gene:7874
680 67256-67260 Gene denotes USP7 Gene:7874
681 67312-67315 Gene denotes p53 Gene:7157
682 67417-67421 Gene denotes USP7 Gene:7874
683 67916-67920 Gene denotes USP7 Gene:7874
684 68131-68135 Gene denotes USP7 Gene:7874
685 67441-67449 Chemical denotes cysteine MESH:D003545
686 67606-67608 Chemical denotes 1H
687 67609-67612 Chemical denotes 15N
688 67713-67721 Chemical denotes Di Lello
689 67286-67291 Disease denotes tumor MESH:D009369
696 68755-68790 Gene denotes Verona integron-encoded MBL (VIM)-2 Gene:100130535
697 68682-68687 Chemical denotes metal MESH:D008670
698 68910-68918 Chemical denotes β-lactam MESH:D047090
699 68719-68722 Disease denotes MBL MESH:C563602
700 68859-68862 Disease denotes MBL MESH:C563602
701 68870-68873 Disease denotes MBL MESH:C563602
704 70682-70692 Chemical denotes lanthanide MESH:D028581
705 70785-70790 Chemical denotes metal MESH:D008670
707 71522-71524 Chemical denotes 1H
719 71984-71988 Chemical denotes EDTA MESH:D004492
720 72001-72015 Chemical denotes deoxythymidine MESH:D013936
721 72017-72024 Chemical denotes dT-EDTA
722 72042-72047 Chemical denotes metal MESH:D008670
723 72061-72065 Chemical denotes Cu2+
724 72069-72073 Chemical denotes Mn2+
725 72087-72094 Chemical denotes dT-EDTA
726 72111-72116 Chemical denotes metal MESH:D008670
727 72202-72217 Chemical denotes oligonucleotide MESH:D009841
728 72616-72623 Chemical denotes dT-EDTA
729 72629-72634 Chemical denotes metal MESH:D008670
742 72819-72830 Gene denotes vasopressin Gene:551
743 72928-72939 Gene denotes vasopressin Gene:551
744 73140-73151 Gene denotes vasopressin Gene:551
745 72778-72789 Chemical denotes Cys-S-S-Cys
746 72840-72843 Chemical denotes His MESH:D006639
747 72844-72848 Chemical denotes Cu2+
748 72849-72852 Chemical denotes His MESH:D006639
749 72983-72987 Chemical denotes Cu2+
750 72996-72998 Chemical denotes 1H
751 73099-73102 Chemical denotes His MESH:D006639
752 73103-73107 Chemical denotes Cu2+
753 73108-73111 Chemical denotes His MESH:D006639
759 73838-73849 Gene denotes thymosin β4 Gene:7114
760 73927-73929 Chemical denotes 1H
761 73930-73933 Chemical denotes 15N
762 74239-74243 Chemical denotes Ni2+
763 74426-74431 Chemical denotes metal MESH:D008670
765 74891-74894 Gene denotes aid Gene:57379
768 75698-75702 Gene denotes pill Gene:8319132
769 75956-75971 Disease denotes crystal defects MESH:D000070657
773 77129-77133 Gene denotes spin Gene:10927
774 77543-77545 Chemical denotes 1H
775 77572-77575 Chemical denotes 13C MESH:C000615229
784 79094-79098 Chemical denotes PMAA MESH:C030613
785 79147-79155 Chemical denotes platinum MESH:D010984
786 79263-79271 Chemical denotes platinum MESH:D010984
787 79375-79383 Chemical denotes platinum MESH:D010984
788 79552-79560 Chemical denotes platinum MESH:D010984
789 79817-79822 Chemical denotes sugar MESH:D000073893
790 79061-79087 Disease denotes fructose hydrophilic block MESH:D006327
791 79322-79334 Disease denotes cytotoxicity MESH:D064420
808 80045-80050 Chemical denotes ester MESH:D004952
809 80390-80414 Chemical denotes Ac-IHVHLQI-CONH2 peptide
810 80462-80466 Chemical denotes Zn2+
811 80467-80470 Chemical denotes HHQ
812 80509-80513 Chemical denotes Zn2+
813 80601-80604 Chemical denotes His MESH:D006639
814 80633-80637 Chemical denotes Zn2+
815 80665-80668 Chemical denotes His MESH:D006639
816 80702-80706 Chemical denotes Zn2+
817 80730-80734 Chemical denotes Zn2+
818 80750-80755 Chemical denotes metal MESH:D008670
819 80892-80911 Chemical denotes histidine nitrogens
820 80951-80961 Chemical denotes histidines MESH:D006639
821 80973-80977 Chemical denotes Zn2+
822 80993-80998 Chemical denotes metal MESH:D008670
823 80999-81010 Chemical denotes imidazolate
825 81200-81204 Gene denotes high Gene:104137
838 82204-82230 Species denotes Mycobacterium tuberculosis Tax:1773
839 82049-82060 Chemical denotes L-Aspartate MESH:D001224
840 82132-82143 Chemical denotes L-aspartate MESH:D001224
841 82165-82174 Chemical denotes β-alanine MESH:D015091
842 82179-82193 Chemical denotes carbon dioxide MESH:D002245
843 82357-82360 Chemical denotes ADC
844 82378-82389 Chemical denotes L-aspartate MESH:D001224
845 82391-82402 Chemical denotes L-aspartate MESH:D001224
846 82454-82465 Chemical denotes L-aspartate MESH:D001224
847 82469-82478 Chemical denotes β-alanine MESH:D015091
848 82512-82523 Chemical denotes L-aspartate MESH:D001224
849 82561-82570 Chemical denotes β-alanine MESH:D015091
856 83483-83486 Gene denotes aid Gene:57379
857 83400-83405 Species denotes human Tax:9606
858 83335-83349 Chemical denotes dithiothreitol MESH:D004229
859 83351-83354 Chemical denotes DTT MESH:D004229
860 83366-83369 Chemical denotes 13C MESH:C000615229
861 83524-83527 Chemical denotes 13C MESH:C000615229
871 85003-85033 Species denotes Human immunodeficiency virus 1 Tax:11676
872 85035-85040 Species denotes HIV-1 Tax:11676
873 84974-84988 Chemical denotes benzodiazepine MESH:D001569
874 85237-85251 Chemical denotes benzodiazepine MESH:D001569
875 85450-85464 Chemical denotes benzodiazepine MESH:D001569
876 85533-85547 Chemical denotes benzodiazepine MESH:D001569
877 85615-85617 Chemical denotes 1H
878 85715-85729 Chemical denotes benzodiazepine MESH:D001569
879 85831-85845 Chemical denotes benzodiazepine MESH:D001569
903 86331-86335 Gene denotes MDM2 Gene:4193
904 86336-86339 Gene denotes p53 Gene:7157
905 86637-86641 Gene denotes MDM2 Gene:4193
906 86642-86645 Gene denotes p53 Gene:7157
907 86825-86829 Gene denotes MDM2 Gene:4193
908 86846-86850 Gene denotes MDM2 Gene:4193
909 86851-86854 Gene denotes p53 Gene:7157
910 87048-87052 Gene denotes MDM2 Gene:4193
911 87502-87506 Gene denotes MDM2 Gene:4193
912 87570-87574 Gene denotes MDM2 Gene:4193
913 86494-86500 Chemical denotes RG7112 MESH:C579783
914 86623-86629 Chemical denotes RG7112 MESH:C579783
915 86745-86751 Chemical denotes RG7112 MESH:C579783
916 86781-86787 Chemical denotes RG7112 MESH:C579783
917 86868-86870 Chemical denotes 1H
918 86871-86874 Chemical denotes 15N
919 86998-87004 Chemical denotes RG7112 MESH:C579783
920 87018-87020 Chemical denotes 1H
921 87021-87024 Chemical denotes 15N
922 87182-87188 Chemical denotes RG7112 MESH:C579783
923 87233-87235 Chemical denotes 1H
924 87236-87239 Chemical denotes 15N
925 86398-86404 Disease denotes cancer MESH:D009369
935 88042-88059 Gene denotes von Hippel–Lindau Gene:7428
936 88061-88064 Gene denotes VHL Gene:7428
937 88120-88126 Gene denotes HIF-1α Gene:3091
938 88231-88237 Gene denotes HIF-1α Gene:3091
939 88287-88291 Gene denotes pVHL Gene:7428
940 88292-88301 Gene denotes elongin C Gene:6921
941 88302-88311 Gene denotes elongin B Gene:6923
942 88431-88435 Gene denotes Carr Gene:407
943 88092-88099 Disease denotes hypoxia MESH:D000860
950 90693-90696 Gene denotes p38 Gene:1432
951 90751-90759 Chemical denotes SB203580 MESH:C093642
952 90846-90854 Chemical denotes SB203580 MESH:C093642
953 90998-91006 Chemical denotes pyridine MESH:C023666
954 91038-91046 Chemical denotes SB203580 MESH:C093642
955 91195-91203 Chemical denotes SB203580 MESH:C093642
963 92113-92117 Gene denotes a 3D Gene:140564
964 92458-92474 Species denotes L. mesenteroides Tax:1245
965 92336-92345 Chemical denotes glycolate MESH:C031149
966 92346-92350 Chemical denotes NAD+ MESH:D009243
967 92413-92420 Chemical denotes glucose MESH:D005947
968 92433-92438 Chemical denotes NADPH MESH:D009249
969 92475-92482 Chemical denotes glucose MESH:D005947
979 93163-93191 Chemical denotes 2-(3′-pyridyl)-benzimidazole
980 93214-93252 Chemical denotes uridine diphosphateN-acetylglucosamine
981 93254-93264 Chemical denotes UDP-GlcNAc
982 93349-93352 Chemical denotes Ile MESH:D007532
983 93354-93357 Chemical denotes Val MESH:D014633
984 93359-93362 Chemical denotes Leu MESH:D007930
985 93375-93378 Chemical denotes Trp MESH:D014364
986 93380-93383 Chemical denotes Phe MESH:D010649
987 93385-93388 Chemical denotes His MESH:D006639
990 93846-93850 Gene denotes Tert Gene:7015
991 93857-93866 Disease denotes Labelling
1006 95062-95065 Gene denotes NS3 Gene:3845
1007 95222-95226 Gene denotes tert Gene:7015
1008 95150-95154 Gene denotes tert Gene:7015
1009 94814-94818 Gene denotes tert Gene:7015
1010 94579-94583 Gene denotes tert Gene:7015
1011 94329-94333 Gene denotes tert Gene:7015
1012 94134-94138 Gene denotes tert Gene:7015
1013 94014-94018 Gene denotes tert Gene:7015
1014 94475-94479 Gene denotes high Gene:104137
1015 94503-94530 Species denotes Bacillus stearothermophilus Tax:1422
1016 95044-95056 Species denotes dengue virus Tax:12637
1017 94310-94312 Chemical denotes 1H
1018 95263-95269 Chemical denotes Val155
1019 95275-95281 Chemical denotes DENpro
1032 95887-95891 Gene denotes NQO2 Gene:4835
1033 96016-96020 Gene denotes NQO2 Gene:4835
1034 95815-95825 Chemical denotes tretazicar MESH:C100099
1035 95827-95866 Chemical denotes (5-(aziridin-1-yl)-2,4-dinitrobenzamide MESH:C100099
1036 95877-95883 Chemical denotes CB1954 MESH:C100099
1037 95994-96004 Chemical denotes tretazicar MESH:C100099
1038 96119-96129 Chemical denotes tretazicar MESH:C100099
1039 96215-96225 Chemical denotes asparagine MESH:D001216
1040 96251-96259 Chemical denotes hydrogen MESH:D006859
1041 96286-96296 Chemical denotes tretazicar MESH:C100099
1042 96311-96320 Chemical denotes aziridine MESH:C033132
1043 96331-96341 Chemical denotes tretazicar MESH:C100099
1058 96805-96809 Gene denotes Brd4 Gene:23476
1059 96867-96871 Gene denotes Brd4 Gene:23476
1060 97024-97028 Gene denotes Brd4 Gene:23476
1061 97882-97886 Gene denotes Brd4 Gene:23476
1062 97887-97890 Gene denotes BD1 Gene:1672
1063 96872-96875 Gene denotes BD1 Gene:1672
1064 96810-96813 Gene denotes BD1 Gene:1672
1065 96937-96955 Chemical denotes triazolopyridazine
1066 97196-97201 Chemical denotes water MESH:D014867
1067 97305-97310 Chemical denotes water MESH:D014867
1068 97412-97430 Chemical denotes triazolopyridazine
1069 97709-97727 Chemical denotes triazolopyridazine
1070 97837-97845 Chemical denotes hydrogen MESH:D006859
1071 97872-97878 Chemical denotes Asn140
1082 98485-98488 Chemical denotes 13C MESH:C000615229
1083 98493-98496 Chemical denotes 15N
1084 98568-98571 Chemical denotes 13C MESH:C000615229
1085 98572-98574 Chemical denotes 1H
1086 98583-98586 Chemical denotes 13C MESH:C000615229
1087 98587-98589 Chemical denotes 1H
1088 98730-98733 Chemical denotes 15N
1089 98734-98737 Chemical denotes 13C MESH:C000615229
1090 98747-98749 Chemical denotes 1H
1091 98750-98752 Chemical denotes 1H
1101 100152-100158 Gene denotes hIFABP Gene:2169
1102 100107-100112 Species denotes human Tax:9606
1103 99374-99376 Chemical denotes 1H
1104 99792-99795 Chemical denotes 15N
1105 99833-99835 Chemical denotes 1H
1106 99931-99939 Chemical denotes hydrogen MESH:D006859
1107 100077-100093 Chemical denotes naphthoate ester
1108 100160-100169 Chemical denotes ketorolac MESH:D020910
1109 100170-100173 Chemical denotes ANS MESH:C027132
1111 100992-100998 Chemical denotes serine MESH:D012694
1120 102812-102820 Species denotes C) media Tax:140785
1123 102663-102666 Chemical denotes 15N
1124 102788-102791 Chemical denotes 13C MESH:C000615229
1125 102793-102796 Chemical denotes 15N
1126 102806-102809 Chemical denotes 15N
1129 103240-103243 Chemical denotes 15N
1131 104652-104657 Species denotes human Tax:9606
1133 104920-104923 Chemical denotes SPs
1138 106819-106821 Chemical denotes 1H
1139 107013-107015 Chemical denotes 1H
1140 107111-107113 Chemical denotes 1H
1141 107190-107192 Chemical denotes 1H
1145 107837-107841 Gene denotes high Gene:104137
1146 107903-107905 Chemical denotes 1H
1147 108013-108019 Chemical denotes helium MESH:D006371
1154 109040-109044 Gene denotes spin Gene:10927
1155 108792-108794 Chemical denotes 1H
1156 108795-108798 Chemical denotes 15N
1157 108802-108804 Chemical denotes 1H
1158 108805-108808 Chemical denotes 13C MESH:C000615229
1159 108879-108881 Chemical denotes 1H
1162 109264-109268 Gene denotes a 2D Gene:11273
1163 109238-109240 Chemical denotes 2D
1166 110715-110717 Gene denotes CS Gene:1431
1167 110456-110459 Disease denotes MDD MESH:D003865
1170 111474-111478 Gene denotes high Gene:104137
1171 111167-111171 Gene denotes high Gene:104137
1173 111831-111835 Gene denotes high Gene:104137
1178 112827-112831 Gene denotes high Gene:104137
1179 112802-112804 Chemical denotes 2D
1180 113020-113023 Chemical denotes 13C MESH:C000615229
1181 113025-113028 Chemical denotes 15N
1183 113864-113868 Gene denotes High Gene:104137

LitCovid-PD-GO-BP

Id Subject Object Predicate Lexical cue
T1 99206-99214 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T2 102750-102761 http://purl.obolibrary.org/obo/GO_0016049 denotes cell growth
T3 102755-102761 http://purl.obolibrary.org/obo/GO_0040007 denotes growth
T4 104462-104474 http://purl.obolibrary.org/obo/GO_0016791 denotes phosphatases
T5 104941-104955 http://purl.obolibrary.org/obo/GO_0019068 denotes viral assembly
T6 110912-110921 http://purl.obolibrary.org/obo/GO_0023052 denotes in signal
T25274 1490-1498 http://purl.obolibrary.org/obo/GO_0007612 denotes learning
T41226 8226-8234 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T32700 8385-8393 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T6950 12222-12230 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T20318 17555-17578 http://purl.obolibrary.org/obo/GO_0006644 denotes phospholipid metabolism
T95169 17568-17578 http://purl.obolibrary.org/obo/GO_0008152 denotes metabolism
T97670 19005-19015 http://purl.obolibrary.org/obo/GO_0008152 denotes metabolism
T44461 21952-21962 http://purl.obolibrary.org/obo/GO_0008152 denotes metabolism
T28937 24095-24118 http://purl.obolibrary.org/obo/GO_0036272 denotes response to gemcitabine
T71924 29128-29138 http://purl.obolibrary.org/obo/GO_0008152 denotes metabolism
T68745 29151-29161 http://purl.obolibrary.org/obo/GO_0008152 denotes metabolism
T3745 29167-29183 http://purl.obolibrary.org/obo/GO_0006629 denotes lipid metabolism
T18679 29173-29183 http://purl.obolibrary.org/obo/GO_0008152 denotes metabolism
T93601 29362-29371 http://purl.obolibrary.org/obo/GO_0023052 denotes in signal
T97672 35436-35451 http://purl.obolibrary.org/obo/GO_0006605 denotes protein targets
T83902 36878-36886 http://purl.obolibrary.org/obo/GO_0007610 denotes behavior
T79912 45855-45864 http://purl.obolibrary.org/obo/GO_0023052 denotes in signal
T6249 51133-51141 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T89047 52112-52120 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T16144 54910-54918 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T55554 55599-55607 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T99470 56032-56040 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T11659 57000-57013 http://purl.obolibrary.org/obo/GO_0006412 denotes translational
T93302 67286-67302 http://purl.obolibrary.org/obo/GO_0051726 denotes tumor suppressor
T21092 68424-68439 http://purl.obolibrary.org/obo/GO_0006605 denotes protein targets
T68138 74347-74355 http://purl.obolibrary.org/obo/GO_0015297 denotes exchange
T51549 79301-79307 http://purl.obolibrary.org/obo/GO_0098739 denotes uptake
T68041 79301-79307 http://purl.obolibrary.org/obo/GO_0098657 denotes uptake
T564 81183-81198 http://purl.obolibrary.org/obo/GO_0016049 denotes cellular growth
T496 81192-81198 http://purl.obolibrary.org/obo/GO_0040007 denotes growth
T3606 90687-90691 http://purl.obolibrary.org/obo/GO_0004707 denotes MAPK
T66733 90906-90910 http://purl.obolibrary.org/obo/GO_0004707 denotes MAPK
T42258 91073-91077 http://purl.obolibrary.org/obo/GO_0004707 denotes MAPK
T6077 91208-91212 http://purl.obolibrary.org/obo/GO_0004707 denotes MAPK

LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T3 4685-4704 Phenotype denotes Alzheimer’s disease http://purl.obolibrary.org/obo/HP_0002511
T4 4863-4882 Phenotype denotes Alzheimer’s disease http://purl.obolibrary.org/obo/HP_0002511
T5 24177-24190 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T6 24950-24963 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T7 26325-26342 Phenotype denotes ovarian carcinoma http://purl.obolibrary.org/obo/HP_0025318
T8 39750-39756 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T9 39849-39857 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T10 39919-39947 Phenotype denotes chronic lymphocytic leukemia http://purl.obolibrary.org/obo/HP_0005550
T11 67286-67291 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T12 79425-79431 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T13 79465-79478 Phenotype denotes breast cancer http://purl.obolibrary.org/obo/HP_0003002
T14 79490-79501 Phenotype denotes lung cancer http://purl.obolibrary.org/obo/HP_0100526
T15 85009-85025 Phenotype denotes immunodeficiency http://purl.obolibrary.org/obo/HP_0002721
T16 86398-86404 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T17 88092-88099 Phenotype denotes hypoxia http://purl.obolibrary.org/obo/HP_0012418
T18 105437-105446 Phenotype denotes Whitehead http://purl.obolibrary.org/obo/HP_0025250
T19 105845-105854 Phenotype denotes Whitehead http://purl.obolibrary.org/obo/HP_0025250
T20 107209-107225 Phenotype denotes highly sensitive http://purl.obolibrary.org/obo/HP_0041092

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T16 0-2 Sentence denotes 1.
T17 3-15 Sentence denotes Introduction
T18 16-112 Sentence denotes The unexpected SARS-CoV-2/COVID-19 outbreak, with over 34 million confirmed cases globally (Oct.
T19 113-299 Sentence denotes 2020) and the struggle for survival in the absence of a proven and efficient treatments, emphasizes the critical need to develop effective, novel, and rapid drug discovery methodologies.
T20 300-434 Sentence denotes Even though the pharmaceutical industry works constantly to discover and develop novel drugs, the process is still slow and expensive.
T21 435-588 Sentence denotes The cost of introducing a new drug has increased steadily, with current cost estimates predicting that a future drug will cost in excess of $2.6 billion.
T22 589-743 Sentence denotes The typical development cost is usually spread out over the course of 14 years [1,2,3], making investment even more difficult (i.e., cost recovery delay).
T23 744-915 Sentence denotes This high investment barrier for drug development is a result of numerous testing phases (Scheme 1), with each phase requiring a statistically significant number of cases.
T24 916-1079 Sentence denotes Although there are several other substantial costs to drug development, that discussion of experimental methods to reduce costs is beyond the scope of this review.
T25 1080-1234 Sentence denotes The emergence of a pandemic and the emergencies it creates worldwide understandably drive and motivate the rapid development and/or optimization of drugs.
T26 1235-1319 Sentence denotes However, patient safety and subsequent earned public trust is a primary requirement.
T27 1320-1575 Sentence denotes Drug redirecting/repurposing (Scheme 1) is an efficient short-cut method in disease treatment that utilizes existing tools, and combines artificial intelligence, machine learning algorithms, and experimental NMR techniques (i.e., “from Bench to Bedside”).
T28 1576-1687 Sentence denotes This process must be relatively rapid and efficient to have any benefit to patients and the health-care system.
T29 1688-1873 Sentence denotes Compared to mass spectrometry and high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) is another powerful technique with several unique advantages [5,6,7,8].
T30 1874-2074 Sentence denotes NMR is intrinsically quantitative, and it provides several different approaches that are routinely utilized to identify and structurally elucidate molecules of interest [9,10,11,12,13,14,15,16,17,18].
T31 2075-2388 Sentence denotes In contrast to mass spectrometry, NMR is non-destructive, non-invasive, has extremely high reproducibility permitting researchers to acquire measurements under different experimental conditions (e.g., temperature, time points, and concentrations) often while the same sample is inside the magnet [19,20,21,22,23].
T32 2389-2572 Sentence denotes NMR can be used in reaction kinetic studies while several consecutive measurements are taken, and while spectral changes (function of the reaction time) are analyzed [24,25,26,27,28].
T33 2573-2636 Sentence denotes Moreover, molecules are studied at the atomic level [29,30,31].
T34 2637-2847 Sentence denotes Unlike other analytical tools, NMR provides dynamic information, and NMR experiments can be carried out under physiological conditions (e.g., atmospheric pressure, temperature, and different pH values) [32,33].
T35 2848-2991 Sentence denotes This is especially important in medical drug design since one must understand the interactions between an enzyme of interest and the ligand(s).
T36 2992-3162 Sentence denotes NMR provides information on the binding affinity of such ligands, details/location of the binding site, and associated structural changes following binding [32,33,34,35].
T37 3163-3292 Sentence denotes These biophysical details are essential when evaluating the potential efficacy of a drug, and during any subsequent optimization.
T38 3293-3390 Sentence denotes The available literature [32,33,34,36] highlights the practicality of NMR in drug design studies.
T39 3391-3606 Sentence denotes For these reasons, NMR spectroscopy is highly sought after in drug development [37,38,39,40,41], for both molecule identification [11,13,14,18,42,43,44,45,46] and structural elucidation [15,16,17,45,47,48,49,50,51].
T40 3607-3822 Sentence denotes NMR has been successfully applied in stereochemistry [52,53,54,55,56] and isomer determination [57,58,59,60,61], in drug-protein interactions studies [62,63,64], and in the evaluation of drug toxicity [65,66,67,68].
T41 3823-3953 Sentence denotes The use of NMR in drug design is not restricted to academic laboratories and gained interest from those in development industries.
T42 3954-4077 Sentence denotes The use of NMR in drug development increased in the late ‘80s, as seen in both scientific and patent literature (Figure 1).
T43 4078-4193 Sentence denotes While scientific interest in NMR is still growing, the number of patents has been decreasing since the early 2000s.
T44 4194-4341 Sentence denotes The top applicants of NMR in pharmaceutical patents are Bristol Myers, AstraZeneca, and Wyeth, with 146, 104, and 67 patent families, respectively.
T45 4342-4497 Sentence denotes In addition to the advantages provided by NMR, it is often used with complementary methods such as X-ray crystallography, HPLC, and mass spectrometry [69].
T46 4498-4705 Sentence denotes An example of this is found in work by Wyss et al. [36], where they combined X-ray crystallography with NMR fragment-based screening to create the first inhibitor candidate for BACE-1 in Alzheimer’s disease.
T47 4706-4891 Sentence denotes BACE-1 is a membrane-anchored aspartic acid protease and is responsible for the production of amyloid beta peptides in neurons related to the progression of Alzheimer’s disease [36,70].
T48 4892-5106 Sentence denotes Using NMR fragment-based screening, Wyss et al. identified isothiourea as binding to BACE-1 and confirmed this observation with the X-ray crystal structure of the complex of a ligand-efficient isothiourea fragment.
T49 5107-5256 Sentence denotes Information obtained from these experiments aided in design optimization, resulting in the selection of iminopyrimidinones as BACE-1 inhibitors [36].
T50 5257-5355 Sentence denotes This is a perfect example of using different complementary methods to maximize scientific outcome.
T51 5356-5453 Sentence denotes However, in order to be efficient, one must know the advantages and disadvantages of each method.
T52 5454-5578 Sentence denotes One of the major issues regarding NMR is the effective size restriction when measuring targets such as proteins above 40kDa.
T53 5579-5782 Sentence denotes Recent progress has extended this mass limit; an example of this is the resolved structure of chaperone SecB in complex with unstructured proPhoA (PDB ID 5JTL) with a total mass of 119kDa using NMR [71].
T54 5783-5940 Sentence denotes In this review, we present practical guideline to use NMR techniques in drug design studies and provide examples of the successful use of NMR in drug-design.
T55 5942-5944 Sentence denotes 2.
T56 5945-5980 Sentence denotes An Introduction to NMR Spectroscopy
T57 5981-6118 Sentence denotes NMR is a versatile tool for studying biomolecules of all kinds and is a unique regarding the biophysical analysis of drugs [72,73,74,75].
T58 6119-6364 Sentence denotes The basic feature of NMR lies in the fact that it inductively detects the Larmor precession of individual nuclei (i.e., spins) which vary because of different atomic, electronic, and chemical environments (i.e., structural atomic relationships).
T59 6365-6449 Sentence denotes Initially, the sample is placed in a strong, static, and homogeneous magnetic field.
T60 6450-6556 Sentence denotes Because spins contain angular momentum, they exhibit Larmor precessions around this static magnetic field.
T61 6557-6724 Sentence denotes A net magnetization builds up over time as the spin population (represented by different energy levels) is minutely differential in the presence of the magnetic field.
T62 6725-6867 Sentence denotes These levels are dictated by the spin quantum number and can be roughly thought of as different orientations with respect to the static field.
T63 6868-7084 Sentence denotes Subsequently, induced electromagnetic fields at radiofrequencies (called RF pulses) are applied transverse to the plane of the static magnetic field, and the net or bulk magnetization undergoes an effective rotation.
T64 7085-7264 Sentence denotes The bulk coherence moves into the transverse plane and the subsequent coherently precessing magnetization vectors induce a detectable alternating voltage in the NMR receiver coil.
T65 7265-7406 Sentence denotes This tiny alternating voltage is amplified and converted from an analog time domain signal to a frequency reading via Fourier transformation.
T66 7407-7637 Sentence denotes These signals are recorded in response to the induced radio-wave pulses (Figure 2) and are representative of the Larmor frequencies that are converted into normalized values termed chemical shifts in order to be field independent.
T67 7638-7849 Sentence denotes This is the final, representative spectroscopic signature of the chemical and magnetic environment of the atom, and it provides detailed atomic resolution information about the molecular structure [76,77,78,79].
T68 7850-8026 Sentence denotes A wealth of information can be derived from the NMR signal made up components such as the chemical shift position, signal linewidth, and observed couplings/multiplet structure.
T69 8027-8252 Sentence denotes The signal contains precise details about the chemical environment of the involved and interacting spins in the structure of the molecule, dynamics of the spins in various timescales, conformational exchange, etc. [80,81,82].
T70 8253-8322 Sentence denotes Any change in the environment of the associated spin can be observed.
T71 8323-8440 Sentence denotes These changes include molecular binding, interactions, and/or exchange between different conformations [20,83,84,85].
T72 8441-8735 Sentence denotes Thus, NMR has been used to study a wide range of functional molecules such as natural products [86,87,88], saccharides [89,90], metabolites [91,92], DNA [93,94], and proteins [95], and its use as an analytical tool in drug design research has increased immensely in recent years (see Figure 1).
T73 8736-8816 Sentence denotes As NMR is non-destructive in nature, the same sample can be analyzed repeatedly.
T74 8817-9090 Sentence denotes NMR can be performed first and then submitted to mass spectrometry (MS); however, the addition of common deuterated NMR solvents (such as D2O) can perturb MS results and should be avoided (e.g., tube-in-tube or by using non-deuterated solvent and running the NMR unlocked).
T75 9091-9275 Sentence denotes In fact, high-performance liquid chromatography (HPLC), ion-trap MS and NMR have been combined to detect the effects of drugs demonstration in urine and blood serum samples [69,96,97].
T76 9276-9455 Sentence denotes Corcoran and Spraul [98] emphasize that liquid chromatography (LC), MS, and NMR utilized in parallel give comprehensive structural data on molecules of novel drugs in development.
T77 9456-9625 Sentence denotes In the following subsections we briefly describe NMR methods that have been used in drug design, and then discuss how NMR principles are used in drug discovery research.
T78 9627-9631 Sentence denotes 2.1.
T79 9632-9664 Sentence denotes One Dimensional NMR Spectroscopy
T80 9665-9764 Sentence denotes The one-dimensional (1D) experiment is by far the most common NMR experiment used for drug studies.
T81 9765-9947 Sentence denotes The 1D acquisition takes the least amount of time, has one of the simplest hardware requirements, and therefore, in most cases, 1D-NMR is more attractive for high throughput studies.
T82 9948-10121 Sentence denotes One dimensional NMR spectroscopy normally incorporates a preparation period, some form of induced excitation to form coherence, and lastly, a signal “read” detection period.
T83 10122-10233 Sentence denotes The preparation period can be modified according to the needs of the experiment or the specifics of the sample.
T84 10234-10403 Sentence denotes Simple 1D NMR is capable of rapidly producing high-quality spectra of drugs and their targets while revealing how the drugs and targets may interact at the atomic level.
T85 10404-10611 Sentence denotes 1D 1H-NMR is extremely effective in drug design studies because it has a (relatively) high sensitivity, it is non-destructive, and because hydrogen atoms are extremely abundant in most molecules of interest.
T86 10612-10777 Sentence denotes Therefore the resulting spectra usually contains a large amount of relevant information and this wealth of data can be acquired in a relatively short period of time.
T87 10778-10929 Sentence denotes The basic 1D 1H-NMR, along with 1D 13C-NMR, 1D 15N-NMR, and 1D 31P-NMR, and their respective uses in drug design/discovery are briefly discussed below.
T88 10931-10937 Sentence denotes 2.1.1.
T89 10938-10947 Sentence denotes 1D 1H-NMR
T90 10948-11149 Sentence denotes The 1H hydrogen isotope is NMR visible, has the highest gyromagnetic ratio (apart from tritium) of all of NMR active nuclei, and is combined with a vast natural abundance in organic chemical compounds.
T91 11150-11225 Sentence denotes This makes the 1D-1H-NMR experiment the most commonly applied NMR approach.
T92 11226-11418 Sentence denotes Moreover, many software databases [99,100,101,102] are well established for 1H-NMR spectra therefore assisting with processing, analyzing, and identifying the detected molecules automatically.
T93 11419-11586 Sentence denotes Since almost all drug discovery and drug development studies are performed on samples dissolved in water, many different solvent suppression methods have been applied.
T94 11587-11630 Sentence denotes The most common is presaturation [103,104].
T95 11631-11731 Sentence denotes The key point of this method is to use a low power induced field at the specific frequency of water.
T96 11732-11799 Sentence denotes This effectively averages out any coherence of the water resonance.
T97 11800-12049 Sentence denotes The experiment is simple for common hardware to perform and easy to set up; however, presaturation has a substantial disadvantage in that signals resonating close to the solvent signal will show decreased intensity [103,104] or may be lost entirely.
T98 12050-12171 Sentence denotes This is due to the fact the even selective pulses or very low power pulses also excite some area around the water signal.
T99 12172-12344 Sentence denotes Also suppressed hydrogen from H2O in solution can exchange with atoms of interest in the molecule and effectively bleed the suppressive spin state to any neighboring atoms.
T100 12345-12497 Sentence denotes The water signal itself is usually broad, so a wider area of suppression is not necessarily undesirable but affects more of the molecule(s) of interest.
T101 12498-12631 Sentence denotes More recent water suppression techniques have been developed such as those based on a scheme known as excitation sculpting [105,106].
T102 12632-12805 Sentence denotes The basic pulse sequence consists of a double pulsed field gradient echo (DPFGE) in each of which a selective component pulse is flanked by two pulsed field gradients [107].
T103 12806-12864 Sentence denotes The particular elements differ for different applications.
T104 12865-13177 Sentence denotes In the case of water suppression known as WATER suppression by GrAdient Tailored Excitation (WATERGATE), this involves an initial encoding gradient along with the middle element; a combination of two selective 90° rotations on the water along with a central non-selective 180° excitation of all resonances [108].
T105 13178-13308 Sentence denotes This is predicated in that water experiences a 360° rotation (effectively nothing) while all other spins experience 180° rotation.
T106 13309-13419 Sentence denotes The application of the second refocusing gradient does not rephase the water and therefore removes the signal.
T107 13420-13508 Sentence denotes The reader is referred to the detailed literature [103,104,109] for further information.
T108 13509-13744 Sentence denotes In principle, a water suppression element (or many elements combined) can be incorporated in any existing pulse sequence to enhance the performance, and it has been implemented in various 1D, 2D, and triple resonance 3D/4D experiments.
T109 13745-13923 Sentence denotes Although 1H is the most sensitive nucleus for NMR yielding strong, sharp signals within a few minutes [110], chemical shift dispersion of 1H is quite narrow (only around 10 ppm).
T110 13924-14029 Sentence denotes This has prompted the consideration of other nuclei such as 13C, 15N, or 31P for resolution improvements.
T111 14031-14037 Sentence denotes 2.1.2.
T112 14038-14048 Sentence denotes 1D 13C-NMR
T113 14049-14178 Sentence denotes Compared with 1H, 13C has a much higher chemical shift dispersion (~200 ppm), however the natural abundance of 13C is low (1.1%).
T114 14179-14343 Sentence denotes Additionally, the gyromagnetic ratio is ~4 times weaker than 1H and therefore 13C spectra are far more difficult to obtain especially for less concentrated samples.
T115 14344-14805 Sentence denotes There are some polarization transfer techniques such as Distortionless Enhancement by Polarization Transfer (DEPT) or Insensitive Nuclei Enhanced by Polarization Transfer (INEPT), which can enhance signal intensity by starting the magnetization on a higher sensitivity and abundance proton and then transferring magnetization to the less sensitive carbon nuclei for subsequent direct detection [111], but this requires additional hardware and acquisition times.
T116 14806-14889 Sentence denotes The use of 1D 13C in drug design studies was illustrated by Tsujimoto et al. [112].
T117 14890-15037 Sentence denotes The goal of the study was to examine if a metabolomics approach based on 1H and 13C offers significant improvements when comparing potential drugs.
T118 15038-15212 Sentence denotes The authors prepared a total of 40 samples with five different citrus-type crude drugs (kijitsu, tohi, chimpi, kippi and seihi) and measured 1D 1H and 1D 13C for each sample.
T119 15213-15485 Sentence denotes While 1H-NMR spectra allowed the identification of three compounds (naringin, sucrose, and β-glucose), using 13C-NMR allowed unambiguous identification of eight additional compounds (naringin, neohesperidin, α- and β-glucose, sucrose, limonene, narirutin, and synephrine).
T120 15486-15646 Sentence denotes The added signal resolution from 13C-NMR spectra allowed researchers to obtain better structural information about the compounds than from 1H-NMR spectra alone.
T121 15648-15654 Sentence denotes 2.1.3.
T122 15655-15665 Sentence denotes 1D 15N-NMR
T123 15666-15785 Sentence denotes In comparison to the previous example, 15N has a lower shift dispersion (~100ppm) than 13C, but higher than that of 1H.
T124 15786-15938 Sentence denotes Here, the situation is unfortunately severely limited due to an even lower natural abundance (0.37%) and a gyromagnetic ratio ~10 times smaller than 1H.
T125 15939-16020 Sentence denotes This means that 15N’s combined sensitivity is around 260,000 times lower than 1H.
T126 16021-16187 Sentence denotes As a result, isotopic enrichment of 15N combined with 1H-mediated enhancement via indirect detection is often needed in order to obtain a satisfactory 1D 15N spectra.
T127 16188-16265 Sentence denotes Similar to 13C, a few methods are available to overcome such low sensitivity.
T128 16266-16440 Sentence denotes One of them focuses on tagging molecules with carboxyl groups using 15N-ethanolamine and later detecting the signal using a 2D heteronuclear correlation NMR experiment [113].
T129 16441-16528 Sentence denotes Currently, novel approaches such as “smart isotope labeling” have been developed [114].
T130 16529-16788 Sentence denotes Also, the SOFAST (Band-Selective Optimized Flip Angle Short Transient) technique can help but results in substantial hardware considerations/drawbacks and often increased concentrations, and/or dramatically longer experiments are still required [115,116,117].
T131 16789-16826 Sentence denotes Promising methods are on the horizon.
T132 16827-17113 Sentence denotes These methods include 15N heteronuclear signal enhancement via Signal Amplification by Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH); however, more work and research are required before such methods can be applied for biomedical purposes [118].
T133 17115-17121 Sentence denotes 2.1.4.
T134 17122-17132 Sentence denotes 1D 31P-NMR
T135 17133-17344 Sentence denotes With a natural abundance of 100% and a gyromagnetic ratio of about 2.5 times smaller than 1H, one may think that phosphorus could be broadly used for NMR experiments regarding the drug discovery and development.
T136 17345-17483 Sentence denotes However, the application of 31P is limited due to the fact that most of the molecules of interest simply do not contain a phosphorus atom.
T137 17484-17647 Sentence denotes Therefore 31P-NMR is usually applicable for studies related to energy, phospholipid metabolism (ATP, NADP), and/or characterization of changes in DNA [94,119,120].
T138 17648-17826 Sentence denotes For example, Overall et al. conducted an experiment in which they showed that 31P solid-state NMR can be used for quantitative analysis of DNA dynamics within live bacteria [94].
T139 17827-17988 Sentence denotes For that, the researchers first prepared untreated cultures of E. coli, and measured them using a Hartmann-Hahn 1H to 31P cross-polarization (31P CP) experiment.
T140 17989-18094 Sentence denotes Afterwards, they measured E. coli treated with ampicillin and maculatin 1.1 (Mac1.1) in a similar manner.
T141 18095-18399 Sentence denotes Spectra obtained from treated bacteria compared to those obtained from untreated bacteria showed alterations in the lineshape, reduced signal intensity at the spectrum’s edges, and a shift in spectral density towards 0 ppm which indicated the increased dynamics of the phosphorus from nucleic acids [94].
T142 18400-18476 Sentence denotes Over time, several innovations have been applied to expand the usage of 31P.
T143 18477-18578 Sentence denotes Like in 13C and 15N labeling of specific biological compounds, incorporation of 31P can also be used.
T144 18579-18796 Sentence denotes In order to achieve that, 2-chloro-4,4,5,5-tetramethyldioxaphospholane (CTMDP) can be used for tagging lipids containing hydroxyl, aldehyde, and carboxyl groups that can later be detected with better resolution [121].
T145 18797-18938 Sentence denotes Another fairly recent method enables toxicological screening of 31P in living cells for several hours without affecting cell viability [122].
T146 18939-19096 Sentence denotes This specific method can be used to observe the changes in energy metabolism in real-time while enabling the evaluation of the effects of administered drugs.
T147 19098-19102 Sentence denotes 2.2.
T148 19103-19137 Sentence denotes Multi-Dimensional NMR Spectroscopy
T149 19138-19311 Sentence denotes NMR experiments are not limited to one-dimensional direct acquisition; they can be extended to multidimensional methods including 2D, 3D, 4D, and even higher dimensionality.
T150 19312-19423 Sentence denotes The focus of this section is common 2D NMR experiments that have been used in drug design and drug development.
T151 19424-19641 Sentence denotes A brief description of Correlation Spectroscopy (COSY), Total Correlation Spectroscopy (TOCSY), and Heteronuclear Multiple Bond Correlation (HMBC), along with their uses in drug design and discovery will be presented.
T152 19643-19649 Sentence denotes 2.2.1.
T153 19650-19663 Sentence denotes 2D 1H,1H-COSY
T154 19664-19741 Sentence denotes COSY is one of the simplest and most frequently used 2D NMR experiment [123].
T155 19742-19842 Sentence denotes It shows the homonuclear coupling of nuclei (i.e., 1H-1H) separated by up to several covalent bonds.
T156 19843-20046 Sentence denotes The pulse sequence consists of a 90° excitation pulse followed by a specific evolution time (t1), a second pulse, and finally a measurement period (t2, not to be confused with relaxation rates or times).
T157 20047-20222 Sentence denotes The second pulse can be 90° or 45° or 135°, depending upon the specific requirements, and respectively yield COSY [124], COSY-45 or COSY-135 functionality (see [125,126,127]).
T158 20223-20391 Sentence denotes A two-dimensional Fourier Transform (FT) yields the final spectra and shows the frequencies for proton (1H) or carbon (in the case of carbon detection) along both axes.
T159 20392-20611 Sentence denotes There are two types of peaks; (I) Diagonal peaks, which represent the peaks of the conventional 1D spectra, and (II) cross-peaks, which have different values in the two frequency axes and are therefore off the diagonal.
T160 20612-20781 Sentence denotes These off diagonal cross-peaks are the most important pieces of information as they mark correlations between pairs of nuclei due to through bond magnetization transfer.
T161 20782-20941 Sentence denotes This helps in identifying which atoms are connected [128], critical for structural elucidation of both known molecules and unknown molecules in solution [129].
T162 20942-21134 Sentence denotes By implementing phase-cycling [130,131], it is also possible to distinguish different types of coupling and yields further helpful information about the chemical structure of a molecule [132].
T163 21135-21228 Sentence denotes As an example, the use of the COSY experiment was presented in the work of Zheng et al. [88].
T164 21229-21440 Sentence denotes The main goal of their work was to investigate potential biological differences and compare the pharmacological effects between Danggui (an herbal drug used in traditional Chinese medicine) and European Danggui.
T165 21441-21575 Sentence denotes For that, Zheng et al. treated blood deficiency rats with Danggui and European Danggui and collected samples of their serum and urine.
T166 21576-21735 Sentence denotes The samples were later measured using 1H-CPMG-NMR, 1H-NOESYPRESAT-1D, 1H,1H-COSY, and 1H,13C-HSQC, and then compared to equivalent spectra from untreated rats.
T167 21736-21972 Sentence denotes The results showed that exposure to Danggui and European Danggui altered the levels of 18 different metabolites, such as lactate, nicotinamide, glycerol and formate, which were involved in a total of seven different metabolism pathways.
T168 21973-22146 Sentence denotes Additionally, it was proven that Danggui and European Danggui have different chemical compositions, with Danggui having better blood-enriching effects than European Danggui.
T169 22148-22154 Sentence denotes 2.2.2.
T170 22155-22169 Sentence denotes 2D 1H,1H-TOCSY
T171 22170-22347 Sentence denotes Total Correlation Spectroscopy (TOCSY) also originally known as the Homonuclear Hartmann Hahn (HOHAHA) experiment can be considered an extension of the 2D 1H,1H-COSY experiment.
T172 22348-22586 Sentence denotes The difference between the two experiments is that a TOCSY experiment will show multiple cross-peaks including indirectly coupled nuclei (i.e., longer range via scalar coupling) throughout the J-coupled spin system of a chemical compound.
T173 22587-22746 Sentence denotes The basic pulse sequence of the TOCSY consists of excitation by a 90° pulse, followed by a free variable evolution period which encodes the indirect dimension.
T174 22747-22876 Sentence denotes This is normally followed by an isotropic mixing sequence to transfer magnetization between spins via the strong scalar coupling.
T175 22877-23003 Sentence denotes The mixing generates in-phase magnetization throughout a spin coupled network of the associated nuclei during the mixing time.
T176 23004-23044 Sentence denotes Lastly, a direct detection is performed.
T177 23045-23280 Sentence denotes A major advantage of the TOCSY experiment is that it detects in-phase magnetization (i.e., pure absorptive line-shape) which is far easier to analyze compared to the anti-phase information in the phase sensitivity COSY-type experiment.
T178 23281-23526 Sentence denotes The isotropic mixing is usually performed using a composite pulse scheme such as WALTZ, MLEV or DIPSI [133,134] pulse train, and can be sandwiched between two z-filters [135] where isotropic mixing is performed on the longitudinal magnetization.
T179 23527-23657 Sentence denotes The most obvious advantage of TOCSY is that all cross-peaks of the same spin system can be observed for whole spin system at once.
T180 23658-23770 Sentence denotes This is useful for identifying the complete network of spins and reducing the ambiguity of any spectral overlap.
T181 23771-23934 Sentence denotes The TOCSY experiment can be produced as 1D with a relatively shorter time and easier analysis compared to 2D but lacks the benefit of multi-dimensional resolution.
T182 23935-24043 Sentence denotes The 2D TOCSY is usually done to resolve spectra overlap [50] when first identifying molecules [136,137,138].
T183 24044-24275 Sentence denotes For example, Jiang et al. used this to predict the response to gemcitabine-carboplatin (GC) chemotherapy in patients with metastatic breast cancer who were previously exposed to treatment with both anthracyclines and taxanes [137].
T184 24276-24392 Sentence denotes For that, researchers collected serum samples from 29 patients prior to treatment and measured them using 1D 1H-NMR.
T185 24393-24539 Sentence denotes Additionally, they conducted 2D NMR experiments such as the 1H,1H-COSY, 1,1H-TOCSY, 1H,13C-HSQC, and 1H,13C-HMBC to help assign serum metabolites.
T186 24540-24786 Sentence denotes After receiving the treatment with gemcitabine-carboplatin, patients were divided into four groups based on the results from the computed tomography: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).
T187 24787-25211 Sentence denotes After comparing NMR results prior to the treatment with the outcome of chemotherapy, the researchers observed lower baseline levels of serum format and acetate in breast cancer patients who progressed with the disease than in those who achieved a clinical benefit from therapy, indicating that those two biomarkers could be used to distinguish between patients who will benefit from GC treatment from those who do not [137].
T188 25213-25219 Sentence denotes 2.2.3.
T189 25220-25234 Sentence denotes 2D 1H,13C-HSQC
T190 25235-25471 Sentence denotes 2D- Heteronuclear Single Quantum Coherence (HSQC) experiments are commonly used to help resolve spectral overlap [139] while providing 13C information without the inherent sensitivity losses involved in 13C direct detection (see below).
T191 25472-25568 Sentence denotes HSQC shows the correlations between directly coupled nuclei [140], e.g., 1H-13C or 1H-15N [140].
T192 25569-25715 Sentence denotes As such, an HSQC spectrum will show clean peaks for each unique proton directly connected to the heteronuclear nuclear atom of interest [140,141].
T193 25716-25887 Sentence denotes In 1H,13C/15N HSQC experiments, the magnetization is transferred from the more sensitive nucleus (I:1H) to the less sensitive nucleus (S:13C/15N) [142,143,144] (Figure 3).
T194 25888-26077 Sentence denotes This is especially useful when applying NMR spectroscopy to drug design, as most drugs are organic (i.e., contain carbon atoms), and the relative abundance of 13C (1.1%) is quite low [143].
T195 26078-26206 Sentence denotes By transferring sensitivity from 1H to 13C, one can circumvent the long experimental time required for 1D 13C experiments [143].
T196 26207-26363 Sentence denotes For example, De Castro et al. [145] studied Ptac2S and its related cytotoxicity to the cisplatin-resistant epithelial ovarian carcinoma (EOC), Skov-3 cells.
T197 26364-26505 Sentence denotes In the study, they used NMR spectroscopy and multi-variate statistical analysis to observe how Skov-3 cells reacted to treatment with Ptac2S.
T198 26506-26734 Sentence denotes In particular, they used 1H,13C-HSQC along with 1H-COSY and Heteronuclear Multiple Bond Correlation (HMBC), and the Human Metabolome Database to assign the chemical shifts of the lipid metabolites present in the studied samples.
T199 26735-26847 Sentence denotes Interestingly, Skov-3 cells treated with Ptac2S produced more pyruvate than Skov-3 cells treated with cisplatin.
T200 26848-27007 Sentence denotes The authors also noticed an unexpected difference in lipid metabolite expression levels between the cells treated with Ptac2S and those treated with cisplatin.
T201 27008-27131 Sentence denotes These results provide a possible explanation for how Ptac2S is able to overcome cisplatin resistance in Skov-3 cells [145].
T202 27133-27139 Sentence denotes 2.2.4.
T203 27140-27155 Sentence denotes 2D 1H, 13C-HMBC
T204 27156-27373 Sentence denotes Heteronuclear 2D experiments are useful for transferring magnetization from sensitive nuclei (i.e., 1H) to less sensitive nuclei (i.e., 13C) [146] thereby reducing the time needed for the acquisition of spectra [147].
T205 27374-27491 Sentence denotes Heteronuclear Single Quantum Coherence (HSQC) will only show one cross peak for each coupled pair [92,128] of nuclei.
T206 27492-27672 Sentence denotes This makes HSQCs useful for assigning the backbone of proteins [148] and in metabolites of complex biofluids [149], whose 1D 1H-NMR spectra can suffer from severe spectral overlap.
T207 27673-27906 Sentence denotes The HMBC technique, while similar to HSQC, is an example of a heteronuclear 2D experiment that reveals correlations between nuclei separated by two or more chemical bonds while also suppressing one-bond correlations at the same time.
T208 27907-28043 Sentence denotes This experiment combined with HSQC is often used to assign NMR spectra for studied molecules in drug design experiments [65,66,137,145].
T209 28044-28262 Sentence denotes As an example, HMBC was used in a recent study by Xu et al. [66] to investigate the changes in the metabolic profiles of rats treated with different dosages of the “RenqingMangjue” pill, a traditional Tibetan medicine.
T210 28263-28513 Sentence denotes In this study, the rats were divided into four groups based on the amount of “RenqingMangjue” administered: low dose group (LD)-83.33 mg/kg/day, middle dose group (MD)-333.33 mg/kg/day, high dose group (HD)-1333.33 mg/kg/day and a control group (NC).
T211 28514-28758 Sentence denotes After 15 days of consecutive administration, half of the rat population was used to collect samples such as serum, kidney, and liver tissue, while the other half underwent an additional 15 days of recovery before the same samples were acquired.
T212 28759-28973 Sentence denotes The samples were measured using 1H-NMR CPMG (an experiment used to suppress signals from larger molecules, see below) [150,151,152] along with 1H,1H-COSY, 1H,13C-HSQC, and 1H,13C-HMBC used for molecules assignment.
T213 28974-29244 Sentence denotes The obtained spectra showed that the “RenqingMangjue” pill alters many metabolites, which are related to a variety of metabolic pathways including energy metabolism, amino acid metabolism, and lipid metabolism indicating potentially harmful effects on kidneys and liver.
T214 29246-29252 Sentence denotes 2.2.5.
T215 29253-29287 Sentence denotes Relaxation-Edited NMR Spectroscopy
T216 29288-29442 Sentence denotes Relaxation in NMR is a phenomenon describing the time dependence involved in signal intensity after an induced RF (radiofrequency) pulse is applied [153].
T217 29443-29643 Sentence denotes After application of a 90° RF pulse, the bulk magnetization will move to the transverse (xy) plane and will gradually return to its original equilibrium position along the longitudinal (z) axis [154].
T218 29644-29711 Sentence denotes This process is described in Figure 4, and is termed T1 relaxation.
T219 29712-29831 Sentence denotes The details are beyond the scope of the manuscript and interested readers are directed to [155] and references therein.
T220 29832-29922 Sentence denotes Relaxation times for NMR are even more complicated and exist in two categories: T1 and T2.
T221 29923-30034 Sentence denotes T1 refers to the rate of longitudinal (or spin-lattice) Z-axis relaxation as the system returns to equilibrium.
T222 30035-30190 Sentence denotes A second component also contributes, i.e., T2 relaxation and refers to the rate of transverse (or spin-spin) relaxation [154] which occurs in the XY plane.
T223 30191-30306 Sentence denotes T2 is independent of the longitudinal relaxation (T1) and represents the loss of coherence in the precessing spins.
T224 30307-30446 Sentence denotes Therefore NMR relaxation spectroscopy can be based on T1 and/or T2 [156], and is collectively referred to as “relaxation edited NMR” [157].
T225 30447-30537 Sentence denotes T1-based methods typically measure and compare the T1 times of the free and bound ligands.
T226 30538-30760 Sentence denotes A common way to measure the T1 value of a small molecule is the inversion recovery experiment [158,159], although other experiments are also available such as ultrafast NMR T1 [160] and saturation inversion recovery [161].
T227 30761-30892 Sentence denotes In general, the shorter T1 the relaxation time the less intense the peak signal will be and the broader the signal linewidth [162].
T228 30893-31125 Sentence denotes The T1 values of free and bound ligand will differ depending on how strongly the ligand binds because molecular interactions with the target will influence the ligand’s molecular motion, and hence, its longitudinal relaxation [156].
T229 31126-31339 Sentence denotes Bound ligands will have smaller T1 values than in their free form because, overall, they will experience slower molecular motion upon interacting with a target [163] therefore behaving like a much larger molecule.
T230 31340-31519 Sentence denotes They can (depending on molecule size) also display a negative NOE difference spectrum (transferred NOE) [164], whereas non-binding ligands normally show small-positive NOEs [156].
T231 31520-31653 Sentence denotes For binding ligands to display negative NOEs, their T1 values must be comparatively longer than the 1/koff value of the target [156].
T232 31654-31791 Sentence denotes T1 relaxation times can be easily used to screen small molecules as ligands for DNA [165] and serve as a basis for HTS experiments [166].
T233 31792-32047 Sentence denotes An experiment related to drug design that utilized 1D and 2D relaxation edited NMR was done by Hajduk et al. [167] in which he and others used 1D and 2D relaxation edited NMR techniques to detect ligands that bind to FK506 binding protein and stromelysin.
T234 32048-32184 Sentence denotes One year earlier, Liu et al. [157] used relaxation edited one-and two-dimensional 1H-NMR spectroscopy to characterize biological fluids.
T235 32185-32320 Sentence denotes Tang et al. [168] extended this by applying relaxation edited NMR Spectroscopy to improve the detection of metabolites in blood plasma.
T236 32321-32530 Sentence denotes More recently, Jaremko et al. commented on available models used to interpret 15N protein relaxation data [169], and even used deficient 15N relaxation data to rapidly calculate the dynamics of proteins [170].
T237 32531-32640 Sentence denotes The T2 relaxation experiment relies on so-called Carr–Purcell–Meiboom–Gill (CPMG) building blocks (Figure 5).
T238 32641-32699 Sentence denotes This pulse sequence is explained with the following steps:
T239 32700-32783 Sentence denotes First, application of a 90° RF pulse creates a transverse (xy plane) magnetization.
T240 32784-32880 Sentence denotes Second, a spin-echo period (delay-180°-delay block) is responsible for Mx/y magnetization decay.
T241 32881-32939 Sentence denotes This period is repeated “n’’ times (CPMG building blocks).
T242 32940-33190 Sentence denotes It is essential to point out that every NMR experiment involving a large number of pulses (e. g. due to the repeating building blocks) is likely to be sensitive to hardware restrictions and small miscalibrations of the duration of the applied pulses.
T243 33191-33386 Sentence denotes To attenuate the unwanted effects of miscalibrations, Meiboom and Gill modified the previously used Carr–Purcell sequence [171] by changing the phase of the applied 180° pulses from x to y [172].
T244 33387-33467 Sentence denotes This procedure can be used to measure T2 relaxation times of any type of nuclei.
T245 33468-33630 Sentence denotes For instance, in the case of 13C, all pulses and acquisitions are applied on 13C channel, while broadband proton decoupling is applied during all pulse sequences.
T246 33631-33691 Sentence denotes It works analogically for different NMR-active nuclei [173].
T247 33692-33878 Sentence denotes In a typical CPMG experiment, the effective transverse relaxation rate, R2,eff, is typically measured by fitting the signal decay as a function of a variable number of CPMG blocks [174].
T248 33879-34059 Sentence denotes The experimental half-height linewidth (d) of a given resonance signal is directly related to T2* (also called as ‘effective’ or “observed’’) by the following equation:(1) d=1π T2*
T249 34060-34241 Sentence denotes T2 represents the transverse relaxation times, and additional broadening comes from the magnetic field inhomogeneities (T2inh), which must be taken into account. (2) 1T2*=1T2+1T2inh
T250 34242-34340 Sentence denotes T2 measurements of ligands are also useful for determining the binding nature of a small molecule.
T251 34341-34511 Sentence denotes The T2 values of small molecules are quite large compared to those of bigger molecules (i.e., proteins) mostly because macromolecules have more spin-spin diffusion [175].
T252 34512-34722 Sentence denotes Bound ligands will, therefore, display shorter T2 values than non-binding ligands because they interact with the target (i.e., protein), adopting similar vibrational and rotational energies to the target [176].
T253 34723-34873 Sentence denotes This interaction is represented by the resonance line broadening in the binding ligand’s spectrum when a receptor is introduced into the sample [156].
T254 34874-35141 Sentence denotes Given the sizable difference of T2 values of binding and non-binding ligands, one can utilize 1D relaxation-edited experiments to distinguish the binding ligands from the non-binding ligands efficiently and effectively based on the differences in the T2 values [167].
T255 35142-35224 Sentence denotes These and other related relaxation edited experiments prove useful in drug design.
T256 35225-35471 Sentence denotes Relaxation edited NMR spectroscopy takes advantage of an inherent atomic property (i.e., the return of bulk magnetization back to equilibrium [177]), so no molecular enrichment (e.g., 15N isotopic enrichment of protein targets) is required [167].
T257 35472-35706 Sentence denotes Furthermore, the slow time scale of NMR relaxation allows the user to manipulate the external conditions (i.e., length and power of pulse) to increase the resolution of targets and potential drugs [155] in NMR drug design experiments.
T258 35707-35923 Sentence denotes However, this slow timescale also sets the lower limit at which NMR drug design experiments can be performed [155], meaning that any external manipulations cannot decrease experimental time below a certain threshold.
T259 35924-35990 Sentence denotes This varies based on the drugs and targets used in the experiment.
T260 35991-36237 Sentence denotes Low drug solubility is also a challenge, as the ligands must be at a sufficiently high concentration to allow detection via NMR, although the use of organic solvents has helped to attenuate this effect in relaxation edited NMR spectroscopy [156].
T261 36238-36329 Sentence denotes For examples of experiments that use different NMR techniques mentioned above, see Table 1.
T262 36331-36333 Sentence denotes 3.
T263 36334-36385 Sentence denotes NMR Methods for Drug Discovery and Drug Development
T264 36386-36483 Sentence denotes As stated, NMR spectroscopy can be fundamental in studying how drugs interact with their targets.
T265 36484-36647 Sentence denotes This has been done mainly via the Fragment Based Drug Design (FBDD) approach, which has two sub-approaches: target- (i.e., protein) based, or ligand- (drug) based.
T266 36648-36791 Sentence denotes Target based screening monitors how the target responds to binding molecules in a method called Structure Activity Relationship (“SAR”) by NMR.
T267 36792-37082 Sentence denotes Ligand (drug)-based screening methods provide ways to observe the binding/non-binding behavior of the drug in approaches such as Saturation Transfer Difference (STD) and other Nuclear Overhauser Effect (NOE) type methods, diffusion-based methods, relaxation-based methods (i.e., T1 and T2).
T268 37083-37198 Sentence denotes Target based screening, ligand (drug) based screening, and their respective methods, are discussed in detail below.
T269 37200-37204 Sentence denotes 3.1.
T270 37205-37245 Sentence denotes NMR in Fragment Based Drug Design (FBDD)
T271 37246-37359 Sentence denotes NMR-based drug discovery can be broadly classified into two groups: chemical and biological (in-cell) categories.
T272 37360-37480 Sentence denotes One of the principal methods of drug discovery using NMR spectroscopy is called fragment-based drug design (FBDD) [194].
T273 37481-37577 Sentence denotes In-cell NMR (biological) based drug discovery techniques will be discussed later in this review.
T274 37578-37746 Sentence denotes FBDD was first reported in 1996 [195] and used throughout the late 1990s as evidenced by the use of keywords related to FBDD in papers published during this time [196].
T275 37747-37850 Sentence denotes The use of FBDD as a viable drug screening technique began to be widely adopted in the mid-2000s [197].
T276 37851-37940 Sentence denotes High Throughput Screening (HTS) is another technique widely used in drug discovery [198].
T277 37941-38058 Sentence denotes HTS analyzes molecules from a chemical library to see which ones are suitable leads [198,199,200,201] (see Figure 6).
T278 38059-38367 Sentence denotes FBDD techniques will screen against a carefully designed fragment library composed of a few thousand molecules (for details on the choice of compounds and design of fragment libraries, see [202,203]) and identified hits are further developed via fragment growing, fragment merging, or fragment linking [194].
T279 38368-38477 Sentence denotes For examples of drugs derived from the FBDD approach that are currently in clinical trials, refer to Table 2.
T280 38478-38670 Sentence denotes HTS has been productive in drug design [204,205], but the method is time and resource intensive [206] and expensive [206] because of the numerous molecules to be examined (~100 million) [207].
T281 38671-38743 Sentence denotes Furthermore, the success rate is only estimated to be at ~50% [204,208].
T282 38744-38990 Sentence denotes Unlike traditional HTS, which can survey a large number of molecules ranging from a few hundred thousand to a few million [209], FBDD usually surveys a few thousand molecules (~1000–15000) from libraries with greater chemical diversity [209,210].
T283 38991-39134 Sentence denotes FBDD is a main-stream screening technique for drug discovery [207,209,211,212,213,214,215,216] and NMR is standard for many FBDD studies [209].
T284 39135-39316 Sentence denotes Additional methods and techniques such as SPR, X-ray crystallography [209,217,218,219,220] etc. have also been used in FBDD studies, accompanied or unaccompanied by NMR experiments.
T285 39317-39396 Sentence denotes For examples of FBDD derived drugs using methods besides NMR, refer to Table 2.
T286 39397-39600 Sentence denotes At the time of writing, and to the best of our knowledge, there are three Food and Drug Administration (FDA)-approved drugs derived from the FBDD approach [221], and over 30 are in clinical trials [222].
T287 39601-39676 Sentence denotes The first marketed drug derived via the FBDD approach is vemurafenib [223].
T288 39677-39864 Sentence denotes Vemurafenib is also the first drug approved for treatment of BRAF-mutant cancer [224], and is reported to exhibit significant clinical benefit for patients with metastatic melanoma [224].
T289 39865-40083 Sentence denotes Venetoclax, a common drug used to treat patients with chronic lymphocytic leukemia [225], is considered the second drug to be discovered using the FBDD approach [221], and ribociclib, a CDK4 inhibitor, the third [221].
T290 40084-40227 Sentence denotes The names, structures, targets/applications, and clinical status of vemurafenib, venetoclax, ribociclib, and other drugs are listed in Table 2.
T291 40228-40375 Sentence denotes As mentioned, NMR spectroscopy can be used in FBDD in two different ways: (1) target (or receptor) based screening, and (2) ligand-based screening.
T292 40376-40481 Sentence denotes With the stated advantages and disadvantages, researchers must select based on their available compounds.
T293 40483-40489 Sentence denotes 3.1.1.
T294 40490-40512 Sentence denotes Target Based Screening
T295 40513-40651 Sentence denotes Target based screening typically utilizes the “SAR by NMR” (structure-activity-relationship by nuclear magnetic resonance) approach [246].
T296 40652-40736 Sentence denotes SAR is primarily used to identify and develop extremely tight-binding ligands [247].
T297 40737-40932 Sentence denotes The ligand to target binding is traditionally monitored via chemical shift changes [247] using a correlation spectroscopy such as 1H-15N HSQC starting with the target and no ligand present [248].
T298 40933-41017 Sentence denotes Multiple spectra for the target are recorded in the presence and absence of ligands.
T299 41018-41180 Sentence denotes The binding ligand will cause chemical shift perturbations in the target, and these perturbations are often easily visualized by overlaying the two spectra [247].
T300 41181-41315 Sentence denotes For example Hajduk et al. investigated the binding interactions of 2-phenylimidazole with the FKBP protein as shown in Figure 7 [249].
T301 41316-41525 Sentence denotes From the overlaid spectra, chemical shift changes are measured, and from the molecular location, extent, and rate of the chemical shift changes, the binding site and affinity of the ligand is calculated [250].
T302 41526-41769 Sentence denotes Then, by following a procedure completely analogous to that of FBDD (see Figure 6), a ligand developed from multiple fragments can be optimized for the binding site of interest, again by monitoring the changes in chemical shifts of the target.
T303 41770-41911 Sentence denotes Several examples of the successful applications of SAR by NMR in drug design research are replete in the scientific literature [204,251,252].
T304 41912-42092 Sentence denotes SAR by NMR spectroscopy allows researchers to observe directly ligand binding [247] in both solution state and solid-state spectra [253], increasing the method’s versatility [254].
T305 42093-42189 Sentence denotes It works particularly well for targeting proteins with adjacent “subpocket” binding sites [248].
T306 42190-42289 Sentence denotes Furthermore, SAR by NMR is cost-effective when combined with HTS (High Throughput Screening) [255].
T307 42290-42465 Sentence denotes SAR by NMR can also be used even when atomic peak assignments in spectra are unknown, though it is much more powerful when the resonance frequency of each atom is known [254].
T308 42466-42794 Sentence denotes The main limitation of SAR by NMR, however, is its inability to distinguish between multiple binding modes (i.e., cleavage of covalent bonds or allosteric changes), and if multiple binding modes are present, it can be difficult to pinpoint the “true” binding site of the ligand solely using data obtained using SAR by NMR [254].
T309 42796-42802 Sentence denotes 3.1.2.
T310 42803-42829 Sentence denotes NMR Ligand-Based Screening
T311 42830-42916 Sentence denotes Ligand-based screening, the second approach of NMR in FBDD, has three main categories:
T312 42917-43087 Sentence denotes 1) Saturation Transfer Difference (STD) and Nuclear Overhauser Effect (NOE) type methods, based on 2) diffusion methods, or 3) relaxation-based methods (i.e., T1 and T2).
T313 43089-43095 Sentence denotes 3.1.3.
T314 43096-43132 Sentence denotes Saturation Transfer Difference (STD)
T315 43133-43324 Sentence denotes Saturation Transfer Difference (STD) NMR depends on the Nuclear Overhauser Effect (NOE), which is often used to enhance the sensitivity of less sensitive nuclei such as 13C and 15N [256,257].
T316 43325-43454 Sentence denotes This increase in sensitivity is possible because of dipolar coupling (i.e., through space interactions of separate nuclei) [257].
T317 43455-43801 Sentence denotes The increase in sensitivity is actually brought about by applying a long, low power radiofrequency pulse that selectively saturates the magnetization [256] of a specific chemical group (i.e., the methyl groups on a protein), which is then given time to transfer to another chemical group via the NOE dipolar coupling within a few angstroms [258].
T318 43802-43962 Sentence denotes The transfer in magnetization is easily visualized on a NMR spectrum that takes the differences in the signal intensities from before and after the irradiation.
T319 43963-44109 Sentence denotes This new spectrum is called a “difference spectrum”, and it reveals what chemical groups interact with the irradiated signal [259] (see Figure 8).
T320 44110-44234 Sentence denotes STD NMR is an application of NOE used to probe the binding of ligands to a specific site within the targeted proteins [256].
T321 44235-44315 Sentence denotes A generic example of detecting ligand binding via STD is presented in Figure 9a.
T322 44316-44631 Sentence denotes The STD NMR method follows the same concepts as a normal NOE experiment: a spectrum of the ligand in the free, non-binding form is recorded, the ligand is allowed to bind to the protein, which has a functional group of interest (i.e., methyls) with a saturated signal from a previous selective radiofrequency pulse.
T323 44632-44836 Sentence denotes The saturated signal travels to the ligand, increasing the intensity of a signal on the ligand spectrum and finally a difference spectrum is used to determine precisely which sections of the ligands bind.
T324 44837-44916 Sentence denotes The difference in peak intensities proves the presence of ligand binding [260].
T325 44917-45022 Sentence denotes Water-Ligand Observed through Gradient Spectroscopy (WaterLOGSY) is a second type of STD (see Figure 9b).
T326 45023-45219 Sentence denotes The main difference with normal STD NMR is that water is the saturated signal [261], and instead of observing lower peak intensities, peak inversions indicate the presence of ligand binding [209].
T327 45220-45398 Sentence denotes For STD NMR to work properly, the ligand concentration must be in large excess (often 100–1000 fold) over the receptor so that effective saturation transfer can take place [260].
T328 45399-45521 Sentence denotes This means that for STD NMR, and WaterLOGSY, only small amounts (µg) of protein are required to get results [261,262,263].
T329 45522-45686 Sentence denotes This is advantageous for researchers, as they can perform STD NMR on a protein of interest, and preserve the rest of the unused sample for future/other experiments.
T330 45687-45751 Sentence denotes Also, the same sample can be used for multiple NMR measurements.
T331 45752-45961 Sentence denotes STD NMR facilitates the differentiation of binding ligands from non-binding ligands because the change in signal (as determined by the difference spectrum) is easy to measure and observe, as shown in Figure 9.
T332 45962-46043 Sentence denotes WaterLOGSY has been extended to study ligand interactions with DNA and RNA [261].
T333 46044-46235 Sentence denotes There are additional NOE-type experiments (trNOE, INPHARMA, SALMON, etc.) used for drug design, and specific details regarding individual methods are found in the scientific literature [264].
T334 46236-46382 Sentence denotes With the pressing search for new antiviral drugs, any techniques for identifying and characterizing novel leads has become increasingly important.
T335 46383-46618 Sentence denotes Benie et al. [265] described the use of saturation transfer difference (STD) NMR spectroscopy [262,266,267,268,269,270,271] to identify and characterize the binding of an antiviral compound to native human rhinovirus serotype 2 (HRV2).
T336 46619-46824 Sentence denotes The experiments demonstrated that it is possible to subject targets of the size and complexity of whole viruses (for a model of an HRV2 particle cut open, cf. the table of contents) to STD NMR experiments.
T337 46825-47067 Sentence denotes The principles of STD NMR have been known for many years [267,268] but it was only recently that the potential of this technique for screening libraries for compounds with binding activity toward protein receptors has been realized [262,266].
T338 47068-47160 Sentence denotes The technique also permitted the analysis of epitopes of ligands bound to receptor proteins.
T339 47161-47293 Sentence denotes Previous NMR studies of virus-ligand interactions used chemical shift titrations, which required very large quantities of the virus.
T340 47294-47356 Sentence denotes This approach was unworkable when studying pathogenic viruses.
T341 47357-47629 Sentence denotes Benie et al. [265] demonstrated that solution state STD methodology not only reduces the amount of virus required by approximately 2 orders of magnitude, but also allows for the identification and characterization of virus-ligand interactions with atomic resolution [272].
T342 47630-47843 Sentence denotes The very large size of viruses makes them particularly attractive for studies by STD NMR, as they inherently yield large line widths allowing for easy irradiation of the virus without affecting the ligand protons.
T343 47844-48014 Sentence denotes Furthermore, because of the larger correlation time of a virus in comparison to an average-sized protein, spin diffusion, and thus saturation transfer, is very efficient.
T344 48015-48255 Sentence denotes The large line width has additional benefits not just for STD-based NMR methods but also for transfer NOESY spectra, as protons from the virus capsid are invisible in the NMR spectra (for an example of a transfer NOESY spectrum, see [265]).
T345 48256-48360 Sentence denotes Moreover, competitive STD titration experiments can be used to determine the Kd value of a ligand [271].
T346 48361-48486 Sentence denotes Analysis of the STD spectra using the group epitope mapping method [271] allows for the determination of the binding epitope.
T347 48487-48609 Sentence denotes STD NMR methods can considerably speed up the determination of the binding epitope for potential antiviral lead compounds.
T348 48610-48812 Sentence denotes Simple STD NMR experiments provide substantial information on the binding of ligands to native viruses and require very small amounts of the virus with measurement times in the range of tens of minutes.
T349 48813-49059 Sentence denotes This allows for a high throughput of ligand samples without significant consumption of viral material because it remains unaffected by the experiments and is easily separated from the low molecular weight ligands by ultra-filtration subsequently.
T350 49060-49172 Sentence denotes In addition to the detection of binding, a complete mapping of the ligand-binding epitope can be achieved [265].
T351 49173-49343 Sentence denotes Noroviruses (NV) are non-enveloped, single-stranded, positive-sense RNA viruses that are the major cause of epidemic outbreaks of gastroenteritis worldwide [273,274,275].
T352 49344-49472 Sentence denotes The viral coat consists of a single protein, VP1, which assembles into a capsid with overall icosahedral symmetry [276,277,278].
T353 49473-49601 Sentence denotes Attachment of human noroviruses to histo-blood group antigens (HBGAs) is thought to be critical for the infection process [279].
T354 49602-49712 Sentence denotes The protruding domains of the VP1 proteins, called P-domains, harbor highly conserved binding sites for HBGAs.
T355 49713-49965 Sentence denotes STD NMR-based epitope mapping was used [262,271] to identify structural features of different core types critical for the binding of synthetic A- and B-tetrasaccharides [280] to virus-like particles (VLPs) of a highly homologous GII.4 strain (Ast6139).
T356 49966-50092 Sentence denotes STD NMR experiments provide a robust and straightforward technique for obtaining ligand binding epitopes at atomic resolution.
T357 50093-50227 Sentence denotes Comparing binding epitopes of related ligands then delivers critical information about structural requirements for ligand recognition.
T358 50228-50395 Sentence denotes Conversely, comparison of binding epitopes of a given ligand binding to wild type, and to mutant proteins reveals the importance of individual amino acids for binding.
T359 50396-50616 Sentence denotes STD NMR experiments with L-Fuc and B-trisaccharide in the presence of wild type and mutant VLPs yield virtually identical binding epitopes and suggest that these two mutations do not significantly alter HBGA recognition.
T360 50617-50886 Sentence denotes The STD NMR approach to characterize binding of HBGA ligands to noroviruses has employed VLPs as targets and thus taken advantage of the large size of VLPs yielding excellent signal-to-noise ratios of the corresponding STD NMR spectra, as demonstrated previously [281].
T361 50888-50894 Sentence denotes 3.1.4.
T362 50895-50945 Sentence denotes Transferred NOE (tr-NOE) in Ligand Based Screening
T363 50946-51044 Sentence denotes The application of the transferred NOE (Tr-NOE) effect was first demonstrated by Bothner-By [282].
T364 51045-51206 Sentence denotes The Tr-NOE is the nuclear Overhauser effect between ligand spins, which are in chemical exchange between the bound and unbound form with the protein or receptor.
T365 51207-51295 Sentence denotes Ligands, which are a mixture of target molecules, are small in size (below 500–1000 Da).
T366 51296-51476 Sentence denotes Since they are usually low molecular weight molecules, they exhibit much shorter correlation times when compared to the receptor and have slow NOE build-ups with no spin diffusion.
T367 51477-51543 Sentence denotes This is the reason they show small positive NOEs in the free form.
T368 51544-51696 Sentence denotes When binding to a protein receptor, the situation changes, where the ligand acquires large correlation times in the bound state with rapid NOE build-up.
T369 51697-51790 Sentence denotes Then they show spin diffusion and a strong negative NOE, which is termed the transferred NOE.
T370 51791-51961 Sentence denotes Signals arising from the protein are usually not observed for large proteins as they are generally kept low in concentration, with ligands in a high excess concentration.
T371 51962-52053 Sentence denotes In addition, most of the time protein signals are suppressed by their very short T2 period.
T372 52054-52422 Sentence denotes It is worthwhile to mention that ligands that are in fast exchange between the bound and the free form (dissociation constants ranging from μM to mM) get enough bound time to transfer the negative NOE from the protein complex to the population of the free molecules, yet usually retain the chemical shift of the free molecule along with the relaxation characteristics.
T373 52423-52607 Sentence denotes In order to observe tr-NOEs, the following condition have to be fulfilled:(3) |Nb∂b|≫|Nf∂f| where N and ∂ represent the number of molecules and the cross-relaxation rate, respectively.
T374 52608-52678 Sentence denotes The subscript b and f represent the bound and free form, respectively.
T375 52679-52780 Sentence denotes Therefore, to observe the tr-NOEs, a high excess concentration of ligands over protein is maintained.
T376 52781-53059 Sentence denotes On the other hand, if the ligand concentration is kept too high, the excess free ligand in solution will exhibit positive NOE, which can result in a significant reduction of the tr-NOESY enhancements due to negative NOE developed by the very small concentration of bound ligand.
T377 53060-53217 Sentence denotes Hence, the preparation of the sample becomes tricky and an optimum ratio between 10–30 to 1 is maintained while considering the dissociation constant values.
T378 53218-53332 Sentence denotes The binding of a ligand to a receptor protein can easily be identified by observing the sign and size of the NOEs.
T379 53333-53500 Sentence denotes There are some distinct experimental features for the discrimination between tr-NOEs from the bound state and NOEs of the ligand in free states like the build-up rate.
T380 53501-53596 Sentence denotes For tr-NOEs, this is in the range of 50 to 100 ms, whereas for small ligands it is much longer.
T381 53597-53725 Sentence denotes There have been various instances of experimental implementations to quickly determine the binding activity of ligand libraries.
T382 53726-53889 Sentence denotes One example was to find the ligand molecule among a library of 10 similar structure polysaccharides that is bioactive in binding with recombinant E-selectin [283].
T383 53890-53975 Sentence denotes This is a protein present in an IgG chimera with a molecular weight of about 220 kDa.
T384 53976-54025 Sentence denotes In this case, two 2D NOESY spectra were recorded.
T385 54026-54278 Sentence denotes The NOESY spectra for the ligand library was measured at several temperatures and it was found that most of the 10 compounds exhibited the weak positive NOEs at 310 K, which was then chosen to differentiate between trNOEs showing large negative values.
T386 54279-54431 Sentence denotes The trNOESY spectra of the ligand library in the presence of protein was recorded at different ratios, such as 5:1, 8:1, 12:1, 15:1, and 20:1, at 310 K.
T387 54432-54535 Sentence denotes In all the ratios, trNOEs were observed; however, the ratio of 15:1 represented the best-case scenario.
T388 54537-54543 Sentence denotes 3.1.5.
T389 54544-54589 Sentence denotes The INPHARMA Method for Pharmacophore Mapping
T390 54590-54808 Sentence denotes The INPHARMA method (see Figure 10) was designed to determine the relative orientation between two competitive ligands in the receptor-binding pocket through the observation of inter-ligand NOE between the two ligands.
T391 54809-54945 Sentence denotes It is a tr-NOE in nature as it is mediated by the bound conformation of the competing ligands and in exchange with the receptor protein.
T392 54946-55121 Sentence denotes The first example was competitive binding and observation of inter-ligand NOE between baccatin III and epothilone A in the presence of tubulin, which acts as a receptor [284].
T393 55122-55197 Sentence denotes Since the observation is on the ligand site, it provides unique advantages.
T394 55198-55289 Sentence denotes The detailed conformation of a ligand-protein complex can be addressed by conventional NMR.
T395 55290-55398 Sentence denotes However, it is time-consuming and demands full solving of the structure and there is also a size limitation.
T396 55399-55454 Sentence denotes From that aspect, ligand-based methods are more useful.
T397 55455-55651 Sentence denotes The only limiting fact is that it should fulfill all the conditions of tr-NOE explained previously in terms of dissociation constant (Kd), fast exchange regime, and proper ligand to protein ratio.
T398 55652-55759 Sentence denotes Then, information on the ligand structure can be derived from tr-NOE build up as a function of mixing time.
T399 55760-55837 Sentence denotes This can be readily explained using the originally proposed schematics [284].
T400 55838-55952 Sentence denotes The NOESY spectrum of a mixture of the two ligands A and B in the presence of the common receptor (T) is recorded.
T401 55953-56204 Sentence denotes Under the situation that each of A and B exhibit competitive binding in a fast exchange regime with the receptor T, intermolecular tr-NOE peaks between the two ligands A and B can then be observed in the NOESY spectrum due to extensive spin diffusion.
T402 56205-56348 Sentence denotes During the NOESY mixing time, the first proton of ligand A (HA) binds to receptor T, which results in transfers of magnetization from HA to HT.
T403 56349-56533 Sentence denotes Subsequently, the complex AT dissociates as they fulfill the dissociation constant range, which creates the opportunity for ligand B to bind to the receptor T at the same binding site.
T404 56534-56639 Sentence denotes This results in the transfer of the magnetization of HT, which had been originally coming from HA, to HB.
T405 56640-56785 Sentence denotes As a result, an inter-molecular correlation HA–HB can be seen, and this inter-molecular NOE will be a function of mixing time as described above.
T406 56786-56922 Sentence denotes The detailed analysis of such intermolecular NOE peaks helps in assessing the relative orientation of each ligand in the binding pocket.
T407 56924-56930 Sentence denotes 3.1.6.
T408 56931-56974 Sentence denotes Diffusion Based Spectroscopy in Drug Design
T409 56975-57093 Sentence denotes Diffusion is the random, translational motion of molecules in solution as a consequence of their thermal energy [285].
T410 57094-57257 Sentence denotes This type of motion is often referred to as “Brownian motion”, a motion that describes molecular movement induced by random collisions between the molecules [286].
T411 57258-57457 Sentence denotes In the presence of a concentration gradient, molecules will naturally move from places of higher concentration to places of lower concentration [287] after a period of time, t, as shown in Figure 11.
T412 57458-57518 Sentence denotes Fick’s Law can be used to model this type of movement [288].
T413 57519-57718 Sentence denotes The distribution of the diffusing molecules is accurately represented by a Gaussian curve, a normal distribution centered at a single point, which gradually “flattens” as t approaches infinity [213].
T414 57719-57814 Sentence denotes The extent to which a molecule diffuses is directly related to its shape, size, and mass [285].
T415 57815-58048 Sentence denotes In homogeneous isotropic solutions, the root mean square distance (zrms) traveled by a molecule is given by following equation [289,290]:zrms=(2Dt)12  where D is the diffusion coefficient of the molecule, and t is the diffusion time.
T416 58049-58403 Sentence denotes Making the assumption that the molecules are solid rigid spheres, the value of D can be calculated according to the famous Einstein-Stokes equation (Equation (2)):(4) D=kbT6πηrs  where kb is the Boltzmann’s constant (1.3807 × 10−23 J/K), T is the absolute temperature, η is the solution viscosity, and rs is the hydrodynamic radius of the molecule [290].
T417 58404-58646 Sentence denotes Equation (1) and Equation (2), however, are not universally applicable; they only apply to molecules that are freely diffusing in isotropic, homogeneous solutions, and importantly that can be accurately described as hard, rigid spheres [285].
T418 58647-58859 Sentence denotes Different molecular geometries and additional modes of diffusion (i.e., restricted and anisotropic) require more advanced mathematics and theory [291,292], but the essential concepts of diffusion remain the same.
T419 58860-59010 Sentence denotes The earliest pulse sequence used to measure diffusion in NMR spectroscopy is the gradient spin echo sequence (SE), developed by Stejskal et al. [293].
T420 59011-59055 Sentence denotes The SE pulse sequence is shown in Figure 12.
T421 59056-59242 Sentence denotes The SE pulse sequence uses a gradient (G) of the externally applied magnetic field, (pulsed field gradient), the first after the 90° pulse, and the other after the 180° refocusing pulse.
T422 59243-59374 Sentence denotes The first gradient pulse (G1) labels or gradient-encodes the NMR-active nuclei based on their physical position in the sample tube.
T423 59375-59521 Sentence denotes If the molecules diffuse during the time period they are not in the correct position to experience the second gradient which re-focuses the spins.
T424 59522-59578 Sentence denotes This is detected via NMR as a signal intensity decrease.
T425 59579-59771 Sentence denotes After a diffusion time (∆), the second gradient pulse is applied to decode the spatial labeling of NMR-active nuclei, obtaining a well-defined spectra of diffusing molecules in solution [294].
T426 59772-59926 Sentence denotes Additional NMR sequences are available for diffusion experiments [295], and are detailed in more comprehensive reviews dealing with the subject [296,297].
T427 59927-60363 Sentence denotes The signal intensity of the diffusing molecules depends on three factors, as described by Equation (3) [294]:(5) I=I0e−Dγ2g2δ2  where I is the observed intensity, I0 the reference intensity (unattenuated signal intensity), D is, of course, the diffusion coefficient referred to earlier, γ is the gyromagnetic ratio of the observed nucleus, g is the strength of the gradient, δ the length of the gradient, and ∆ the diffusion time [294].
T428 60364-60552 Sentence denotes From Equation (3), it is easy to see that the signal intensity decreases exponentially with time, so it is vital to optimize the values of g, δ, and ∆ for diffusion NMR measurements [294].
T429 60553-60719 Sentence denotes The drug design approach based on diffusion NMR is basically a screening technique used to differentiate the binding ligands (drug) from non-binding components [264].
T430 60720-60951 Sentence denotes Ligands able to bind should have significantly different diffusion coefficients (D) compared to non-binding ligands [297], i.e., the diffusion coefficients of binding ligands will be smaller than those of non-binding ligands [264].
T431 60952-61062 Sentence denotes Thus, diffusion-based NMR is a way of effectively “filtering” and identifying which ligands are binding [264].
T432 61063-61163 Sentence denotes Diffusion-based NMR spectroscopy has advantages in ligand based screening applied to drug discovery.
T433 61164-61298 Sentence denotes For example, Diffusion Ordered Spectroscopy (DOSY) does not require prior separation/purification of the ligand/target solution [298].
T434 61299-61711 Sentence denotes Diffusion based NMR allows simultaneous determination of diffusion coefficients in multicomponent systems containing large molecules (i.e., proteins) and possible binding partners (i.e., small drug compounds) [285], and no special labeling or contrasting agents are required, though their use is not exclusively inhibited (for an example of the use of labeled compounds in diffusion NMR spectroscopy, see [299]).
T435 61712-61830 Sentence denotes A problem occurs when there is significant chemical shift overlap between the binding molecule signals and the target.
T436 61831-62005 Sentence denotes This situation makes it hard to distinguish the NMR signals [300], and the calculations typically assign an intermediate value to the diffusion rate (i.e., one gets a smear).
T437 62006-62138 Sentence denotes Multidimensional diffusion NMR pulse sequences are available [301], which may help resolve spectral overlap in 1D experiments [300].
T438 62139-62237 Sentence denotes Another issue is that molecules in chemical databases may have generally low solubility [302,303].
T439 62238-62380 Sentence denotes Low solubility decreases the overall signal intensity and therefore makes accurately measuring diffusion experiments far more difficult [304].
T440 62381-62553 Sentence denotes There are many examples demonstrating the successful application of diffusion NMR in examining drugs of pharmaceutical interest [305], and ligand-target interactions [167].
T441 62554-62712 Sentence denotes Hajduk et al. [167] exploited the changes in diffusion rates to detect ligands that bind to the FK506 binding protein and the catalytic domain of stromelysin.
T442 62713-62978 Sentence denotes Nishimura et al. [306] utilized DOSY, in combination with NOESY to determine the orientation of two guest molecules, p-ethoxyiodobenzene and 2-iodo-6-methoxynaphthalene, within a host composed of a tetrakis(4-hydroxyphenyl)-cavitand and a tetra(4-pyridyl)-cavitand.
T443 62979-63210 Sentence denotes Furthermore, Matthias et al. [307] used 1H molecular diffusion and 19F spin diffusion to probe the drug loading properties of the Rf-PEG hydrogel for 5-fluorouracil (FU) and 1,3-dimethyl-5-fluorouracil (DMFU), two anticancer drugs.
T444 63211-63363 Sentence denotes DOSY can be combined with Saturation Transfer Difference (STD, discussed earlier in this review) to yield new insights about ligand-target interactions.
T445 63364-63516 Sentence denotes Kramer et al. [308] combined STD with DOSY to analyze a mixture composed of wheat germ agglutinin and two derivatives of N-acetyl glucosamine (ligands).
T446 63517-63621 Sentence denotes Using this new technique they were able to obtain high quality spectra of the components in the mixture.
T447 63622-63744 Sentence denotes Tanoli et al. [309] also combined STD and DOSY to explore the interactions of smaller molecules with bovine serum albumin.
T448 63745-63886 Sentence denotes These are just a few examples to show that diffusion NMR spectroscopy has played, and will continue to play, a prominent role in drug design.
T449 63888-63892 Sentence denotes 3.2.
T450 63893-63949 Sentence denotes NMR and In Silico Screening-Two Complementary Approaches
T451 63950-64160 Sentence denotes In silico (virtual) screening is now a standard technique in drug design and discovery [310] that has been in use since at least 1991 [311], though the exact origin of the phrase “in silico” is not clear [312].
T452 64161-64530 Sentence denotes The nearly ubiquitous use of virtual screening is due to its efficiency in searching massive chemical databases in order to generate lead molecules [313] that inhibit protein-protein interactions [314], and its ability to help identity ligand (drug) binding sites on the target of interest [310] to lend insight to the mechanisms of action for lead compounds [315,316].
T453 64531-64749 Sentence denotes Virtual screening is often accompanied by in vitro or in vivo techniques for pharmacology drug research [312], to increase drug throughput, helping to reduce the time and cost of developing novel drug candidates [317].
T454 64750-64864 Sentence denotes Virtual screening has also been used to identify candidates for anti-viral drugs [318] and anticancer drugs [319].
T455 64865-64945 Sentence denotes Several chemical databases are available both for public and academic use [320].
T456 64946-65126 Sentence denotes Virtual screening is properly identified as a high-throughput screening (HTS) technique [321], though using its full capacity as an HTS technique is not required for most purposes.
T457 65127-65407 Sentence denotes Virtual screening requires a minimum of two inputs, (1) a three-dimensional model of the ligand (drug), and (2) a three-dimensional model of the receptor (protein) [322], the latter generated from the atomic studies of proteins via X-ray crystallography or NMR spectroscopy [323].
T458 65408-65705 Sentence denotes Virtual screening is not a truly “stand-alone” technique and has often been combined with additional biophysical techniques besides NMR spectroscopy and/or X-ray crystallography [324], such as differential scanning fluorimetry [325], fluorescence polarization, and surface plasmon resonance [324].
T459 65706-65878 Sentence denotes In this section, we briefly introduce how virtual screening has been combined with NMR spectroscopy, and how they are complementary approaches to each other in drug design.
T460 65879-66073 Sentence denotes The complete details of how virtual screening works, and how it applies to drug design outside of its combination with NMR is well documented in additional reviews [310,322,326,327,328,329,330].
T461 66074-66341 Sentence denotes A prime example of the complementarity between NMR screening and virtual docking is found in the work of Chen et al. [331], in which the authors sought to target the A2A adenosine receptor (A2AAR) protein, a drug target for the treatment of Parkinson’s disease [332].
T462 66342-66507 Sentence denotes They used virtual screening and an NMR-based screening method against the same 500 molecules in a fragment library so they could compare the results of both methods.
T463 66508-66779 Sentence denotes The virtual screen successfully predicted (based on calculated binding affinities) four out of the five orthosteric ligands discovered by NMR that were within the top 5% of the fragment library, showing that the two separate methods can give similar and reliable results.
T464 66780-67084 Sentence denotes Later on, Chen et al. discovered that virtual screening picked up three additional fragments that remained undetected by the NMR-based method, and were, in fact, A2AAR ligands; this shows that though neither method is flawless, they are still perfectly complementary approaches for drug design [322,331].
T465 67085-67322 Sentence denotes In another scientific work that integrated NMR with virtual screening, Di Lello et al. [333] found small molecular inhibitors of the enzyme ubiquitin specific protease 7 (USP7), a key regulator of the tumor suppressor protein, p53 [334].
T466 67323-67467 Sentence denotes A fragment screen by NMR revealed a series of small molecules that bind in the active site of USP7 near the catalytic cysteine (amino acid 223).
T467 67468-67712 Sentence denotes A ligand-based virtual screen utilizing the fastROCS program identified ~30 hit molecules, several of which were further characterized by 1H-15N TROSY chemical shift perturbation and line broadening to probe the binding site of the active hits.
T468 67713-67930 Sentence denotes Di Lello. also tested the active compounds against EOL-1 cells to verify the hits as identified by virtual screening and further characterized by NMR, showing that the active compounds do indeed inhibit USP7 activity.
T469 67931-68177 Sentence denotes Through additional study of the active molecules and further optimization of their structures, they eventually discovered a series of ligands that bind in the “palm” region of the catalytic domain of USP7, inhibiting its catalytic activity [333].
T470 68178-68330 Sentence denotes This study clearly demonstrates that NMR screening-based techniques can be combined with virtual screening to find viable drugs for targets of interest.
T471 68331-68580 Sentence denotes Additional examples of the successful integration of NMR and virtual screening as applied to protein targets are also found in the literature, further demonstrating the practicality and complementarity of virtual screening and NMR [329,335,336,337].
T472 68581-68998 Sentence denotes For example, Li et al. [338] used virtual screening filtered by NMR to identify and characterize non-metal chelating metallo-β-lactamase (MBL) inhibitors, and in particular, Verona integron-encoded MBL (VIM)-2, when previously there were no clinically significant inhibitors of MBL, since MBL enzymes hydrolyse many, if not all, β-lactam antibacterials compounds specifically designed to inhibit their activity [339].
T473 68999-69120 Sentence denotes Furthermore, Shan et al. [340] and Bertini et al. [337] both used virtual screening and NMR, in their respective studies.
T474 69121-69315 Sentence denotes Through the combined use of NMR and virtual screening, Shan et al. was able to identify, design, and synthesize novel PDZ domain inhibitors, which are proteins implicated in tumorigenesis [340].
T475 69316-69487 Sentence denotes Bertini et al. was able to combine NMR to study the interaction of ligands with metalloproteinases, using known inhibitors of metalloproteinases as a starting point [337].
T476 69488-69679 Sentence denotes While HSQC NOESY NMR data provided structural and spatial constraints for the proposed 3D models, virtual screening was used to refine the models, and to probe the ligand-protein interaction.
T477 69680-69916 Sentence denotes In each case (i.e., ligand-protein interaction), Bertini et al. was able to obtain a well-defined ligand conformation in the protein binding site, thus offering a viable alternative to other approaches described in the literature [337].
T478 69917-70079 Sentence denotes Clearly, combining virtual screening with NMR-based methods is advantageous in studying how ligands (drugs) bind and interact with targets (proteins) of interest.
T479 70081-70085 Sentence denotes 3.3.
T480 70086-70126 Sentence denotes Paramagnetic Resonance in Drug Discovery
T481 70127-70341 Sentence denotes Paramagnetic NMR (PNMR) can also play a prominent role in drug discovery [341], as PNMR can provide key structural information in situations where crystal structures cannot due to the weak binding of ligands [341].
T482 70342-70459 Sentence denotes PNMR can be used to quantify the binding between ligands and large biomolecules such as proteins, DNA, and RNA [342].
T483 70460-70746 Sentence denotes PNMR depends on the presence of a group (called the paramagnetic center) with an unpaired electron [343], and since many naturally occurring biomolecules and organic compounds lack a paramagnetic center, one such as caged lanthanide (CLaNP) [344], must be introduced artificially [341].
T484 70747-70932 Sentence denotes Once the paramagnetic center (often a metal ion) is present, paramagnetic effects can be used to measure the distance and the relative orientation (i.e., angle) between molecules [345].
T485 70933-71022 Sentence denotes This information is crucial when it comes to determining how ligands and substrates bind.
T486 71023-71119 Sentence denotes Thus, PNMR is quite a useful technique for drug discovery when a paramagnetic center is present.
T487 71120-71353 Sentence denotes The most relevant consequence of PNMR for drug discovery is paramagnetic relaxation enhancement (PRE), although there are a number of studies demonstrating the use of pseudocontact shift (PCS) effect in drug discovery research [341].
T488 71354-71597 Sentence denotes Paramagnetic relaxation enhancement (PRE) is proportional to the inverse sixth power of the distance between the paramagnetic center and the nucleus of interest (i.e., 1H), although it does not reveal anything about relative orientation [341].
T489 71598-71674 Sentence denotes PRE can give quantitative information in the range of 10–25 Angstroms [346].
T490 71675-71862 Sentence denotes Several researchers have taken advantage of this outstanding property to study the structural and dynamic properties of complex biomolecular machineries in their native environment [347].
T491 71863-72218 Sentence denotes For example, Iwahara et al. (2003) demonstrated that a protein’s binding polarity to DNA can be determined by PRE, using EDTA-derivatized deoxythymidine (dT-EDTA) with a chelated metal ion (such as Cu2+ or Mn2+) as a probe. dT-EDTA with a chelated metal ion is a convenient choice, as it can be inserted into any position of a synthesized oligonucleotide.
T492 72219-72342 Sentence denotes With data derived from the PRE effect, one can easily determine the polarity of the protein (or drug) binding to DNA [348].
T493 72343-72650 Sentence denotes Several researchers have investigated DNA as a drug target [349], and the study of Iwahara et al. clearly demonstrates, and even indicates, that PRE can potentially be used to study the interactions between a drug and DNA [348], provided that a paramagnetic center such as dT-EDTA or a metal ion is present.
T494 72651-72759 Sentence denotes Brasuń et al. [350] also used PRE derived distances between a paramagnetic center and a nucleus of interest.
T495 72760-72940 Sentence denotes They replaced the Cys-S-S-Cys bridge found in oxytocin and vasopressin with the His-Cu2+-His motif to investigate if doing so would alter the stability of oxytocin and vasopressin.
T496 72941-73152 Sentence denotes They determined the distances between the Cu2+ ion and 1H nuclei (possible because of PRE), and used these values to generate three-dimensional models of the His-Cu2+-His motifs in both oxytocin and vasopressin.
T497 73153-73475 Sentence denotes In doing so, they indicated that such an approach using PRE can help in designing new biologically active compounds [350], and hence in drug discovery research, as many drug discovery studies require a reliable models for the successful generations of hit-lead molecules, especially in the case of in silico docking [351].
T498 73476-73571 Sentence denotes This study again proves the usefulness of PRE, and therefore, PNMR, in drug discovery research.
T499 73572-73713 Sentence denotes In two additional studies, Huang et al. [352,353] used PRE in their individual studies of protein binding and protein dynamics, respectively.
T500 73714-73877 Sentence denotes In the Huang et al. case [352], these authors used PRE to establish a model of the binding between the G-actin protein, and thymosin β4, an actin- binding protein.
T501 73878-74046 Sentence denotes Using PRE determined constraints (distances) and 1H-15N HSQC, they were able to establish a well-converging docking structure of the G-actin/thymonsin β4 complex [352].
T502 74047-74271 Sentence denotes On the other hand Huang et al. [353] did not measure protein binding, but studied the conformational changes and dynamics of select large membrane proteins utilizing 19F-NMR spectroscopy, and Ni2+ as the paramagnetic center.
T503 74272-74787 Sentence denotes Through a series of extensive experiments, they showed that conformational exchange rates of membrane proteins can be determined from measurements of the metal-enhanced longitudinal relaxation (i.e., PRE) of the 19F nuclei [353], thus yielding additional information (i.e., protein conformation dynamics) that could be utilized in drug discovery projects targeting proteins (i.e., understanding how the protein changes shape based on its environment can be used to find potential binding sites for drug candidates).
T504 74788-75051 Sentence denotes All these examples prove that PNMR is powerful approach in drug discovery research, given that PRE can aid in generating trustworthy models of interacting molecules, and that it can help researchers understand better how the molecules interact in the first place.
T505 75053-75057 Sentence denotes 3.4.
T506 75058-75091 Sentence denotes Solid State NMR in Drug Discovery
T507 75092-75242 Sentence denotes Since the late 1970s solid state NMR (ssNMR) has demonstrated its usefulness in complex biomolecular systems such as collagen or lipid bilayers [354].
T508 75243-75492 Sentence denotes However, over the past years ssNMR has gained attention in the field of drug design and is slowly becoming a commonly used technique as its proving to be a powerful tool for structural analysis of membrane proteins and amyloid fibrils [354,355,356].
T509 75493-75571 Sentence denotes ssNMR is becoming a more attractive alternative for several different reasons.
T510 75572-75717 Sentence denotes One of them is the fact that it enables the characterization of a chemical compound in a solid-state form such as in a tablet/pill [356,357,358].
T511 75718-76361 Sentence denotes Moreover, ssNMR is not only restricted to analyzing the chemical structure but it can also provide insight into the physical properties of a compound such as polymorphism (different crystalline structures of the same compound), disorder (crystal defects and amorphous solids in the compound) or the presence of cocrystals (multicomponent crystal made of a compound and one or more small organic molecules) [356,357]. ssNMR can also be used to quantify the amount of crystalline against the amount of amorphous material in the sample to establish phase purity (the amount of desired phase separated from other, undesirable phase) [356,357,358].
T512 76362-76442 Sentence denotes ssNMR differs from liquid state NMR by the presence of anisotropic interactions.
T513 76443-76538 Sentence denotes In liquids NMR these effects are averaged to zero as a consequence of rapid molecular tumbling.
T514 76539-76896 Sentence denotes In solid state however, the molecules are not tumbling rapidly and the residual effects of anisotropic (orientation depended) interactions such as anisotropic chemical shift, magnetic dipolar coupling, and quadrupolar coupling could be observed in the form of broad peaks, with could be much wider than the chemical shift range of the nucleus [355,358,359].
T515 76897-77082 Sentence denotes As a results, there has been a constant effort to improve the sensitivity and resolution of solid state NMR spectra, which increased the potential of ssNMR in future applications [360].
T516 77083-77188 Sentence denotes One of the methods that works for nuclei with spin value of I = 1/2 is called magic-angle spinning (MAS).
T517 77189-77307 Sentence denotes It increases the resolution by rapidly rotating the sample around a fixed (or so-called magic) angle of 54.736° [360].
T518 77308-77399 Sentence denotes This method can be combined with decoupling, to remove the dipolar couplings between spins.
T519 77400-77586 Sentence denotes This is done by applying radiofrequency pulses or cross-polarization (CP) transfer of magnetization from abundant and sensitive nuclei such as 1H to less sensitive such as 13C [328,333].
T520 77587-77664 Sentence denotes A broader comparison between ssNMR and liquid state NMR is provided in [361].
T521 77665-77754 Sentence denotes As mentioned before, ssNMR can provide information about membranes and membrane proteins.
T522 77755-78187 Sentence denotes For this reason, ssNMR can be used to detect interactions of ligands with receptors embedded to the membrane which enables the mapping of binding site of a receptor by utilizing CP-MAS (cross-polarization magic-angle spinning) NMR and site specific mutagenesis [355]. ssNMR can provide the conformation of ligands bound to the receptor which can then be used to optimize future drug in terms of better affinity and efficiency [355].
T523 78188-78345 Sentence denotes Since ssNMR is also applicable to amyloid research, it can be used for probing polypeptide structures of amyloid and intermolecular contacts between fibrils.
T524 78346-78461 Sentence denotes The potential is for the design a drug that will inhibit the process of aggregation of proteins and peptides [355].
T525 78462-78672 Sentence denotes Lastly, since ssNMR gains insight into physical properties of a chemical compound it can be used for control of the process of formulation and processing of a drug to help assess the purity of a compound [358].
T526 78673-78836 Sentence denotes An example of ssNMR application related to drug design is the work of Callari et al., who monitored the effect of drug loading on the properties of micelles [362].
T527 78837-79023 Sentence denotes Polymer micelles are widely used as nano-carries for drug delivery, but so far the effects of drug loading on the morphology of a drug carrier had not been thoroughly investigated [362].
T528 79024-79177 Sentence denotes They created a model consisting of a fructose hydrophilic block and a PMAA block (micelle), to which a different amount of platinum complex was anchored.
T529 79178-79335 Sentence denotes The results from this experiment showed that micelles loaded with a higher amount of platinum complex had reduced cellular uptake, release, and cytotoxicity.
T530 79336-79569 Sentence denotes The micelles with a lower load (LL) of platinum complex were more effective at targeting cancer cells (of cell lines MDA-MB-231 (breast cancer) and A549 (lung cancer) than the micelles with a higher load (HL) of the platinum complex.
T531 79570-79703 Sentence denotes This is evidenced by the lower IC50 (half maximal inhibitory concentration) values of the LL micelles as compared to the HL micelles.
T532 79704-79856 Sentence denotes Both of those results could be related to the micellar structure and their potential for interaction between the sugar moieties and the cell wall [362].
T533 79857-80062 Sentence denotes Another example of practical application of ssNMR is the work of Lee and colleagues [363] in which they investigated the structure of a designed zinc-binding amyloid fibril that catalyzed ester hydrolysis.
T534 80063-80196 Sentence denotes Metals ions such as zinc where found to affect the process of protein aggregation which resulted in arise of amyloid like structures.
T535 80197-80355 Sentence denotes Therefore, understanding the processes of aggregation and the factors related to them is crucial for creation of new drugs for amyloid related diseases [364].
T536 80356-80484 Sentence denotes In the experiment Lee et al. used Ac-IHVHLQI-CONH2 peptide (referred as HHQ) to form fibrils with varying Zn2+:HHQ molar ratios.
T537 80485-80715 Sentence denotes The results showed that Zn2+-bound HHQ fibrils form parallel-in-register form of packing β-strand in each sheet and His residues are coordinated to Zn2+ via Nδ1, while half of the His residues are also coordinated to Zn2+ via Nε2.
T538 80716-80774 Sentence denotes Additionally, Zn2+ binds in a 1:1 metal ion/peptide ratio.
T539 80775-80938 Sentence denotes After further analysis using structural bioinformatics, it was concluded that each zinc ion was coordinated by three histidine nitrogens from two adjacent strands.
T540 80939-81023 Sentence denotes Half of all histidines bridged to Zn2+ ions forming a metal–imidazolate chain [363].
T541 81025-81029 Sentence denotes 3.5.
T542 81030-81059 Sentence denotes NMR Validation in Drug Design
T543 81060-81243 Sentence denotes A “hit” is a molecule identified from a screening technique (HTS, FBDD, etc) as having a desirable effect (i.e., decreased cellular growth, high affinity score) on a target [365,366].
T544 81244-81425 Sentence denotes However, the question of whether the activity is related to actual binding to the target, or to interference with one of the components of the assay readout mechanism, is uncertain.
T545 81426-81462 Sentence denotes Thus, a validation step is required.
T546 81463-81626 Sentence denotes Hit-validation is therefore the process of confirming, or validating, that the molecule(s) identified previously have on target activity and selectivity [367,368].
T547 81627-81715 Sentence denotes One of the highest-impacts of NMR on drug discovery is the use as a hit-validation tool.
T548 81716-81888 Sentence denotes Though the hit-validation or confirmation of drugs is mostly limited to the solution state [369], this aspect of NMR truly is a “gold standard” technique in drug discovery.
T549 81889-82231 Sentence denotes NMR by itself is a powerful tool for drug validation as in the case of Sharma et al. (2012) [370] who sought to identify potential drug-like inhibitors against L-Aspartate α-Decarboxylase (ADC) an enzyme responsible for the decarboxylation of L-aspartate in order to generate β-alanine and carbon dioxide [371], in Mycobacterium tuberculosis.
T550 82232-82339 Sentence denotes They began with known inhibitors of ADC, and developed a protocol to measure the enzymatic activity of ADC.
T551 82340-82632 Sentence denotes Upon addition of ADC to a solution of L-aspartate, L-aspartate gradually disappeared because ADC was converted to L-aspartate to β-alanine; therefore the peak intensity of L-aspartate decreased, and the peak intensity of β-alanine increased in the presence of ADC (no inhibitor drug present).
T552 82633-82861 Sentence denotes Using this newly developed NMR-based protocol allowed direct measurement of ADC enzymatic activity, and Sharma et al. were able to confirm the enzymatic inhibiting activity of seven previously discovered inhibitors of ADC [370].
T553 82862-82999 Sentence denotes This study demonstrated that NMR can be an effective validation tool for known drugs and for new drugs generated by a screening approach.
T554 83000-83086 Sentence denotes NMR is also able to remove false positives that emerge from biochemical screens [372].
T555 83087-83423 Sentence denotes For example, an aptly named technique called A La Assay to detect Reactive Molecules by Nuclear Magnetic Resonance (ALARM NMR) is able to eliminate false positives from HTS methods [373], and in the presence of a test compound or mixture, measures dithiothreitol (DTT)-dependent 13C chemical shift changes of the human La antigen [373].
T556 83424-83651 Sentence denotes Dahlin et al. provided an updated protocol of ALARM NMR to aid researchers in the production of the 13C-labeled La antigen reporter protein, in testing compounds with the La protein, and in the analysis of obtained NMR spectra.
T557 83652-83721 Sentence denotes Using ALARM NMR prioritized hits identified from HTS screening [374].
T558 83722-84050 Sentence denotes An example of ALARM NMR is found in the work of Dahlin et al., where they used this technique to test molecules that were assumed to be inhibitors of histone acetyltransferase (HAT) inhibitors, and from their studies, actually discovered that 65% (15 out of 23) of the most commonly reported HAT inhibitors were actually faulty.
T559 84051-84163 Sentence denotes They were actually nonselective interference compounds, not necessarily specific to the inhibition of HAT [375].
T560 84164-84343 Sentence denotes Thus, ALARM NMR (and NMR in general) served as a useful validation method, especially for unvalidated hits identified from biochemical screens [372] or other screening techniques.
T561 84344-84483 Sentence denotes The last example highlights the need for cross validation, or the combination of two or more techniques to verify identified chemical hits.
T562 84484-84550 Sentence denotes Of course, NMR is not the sole technique used for drug validation.
T563 84551-84793 Sentence denotes Most often, NMR drug validation is coupled with additional methods [367] such as surface plasmon resonance (SPR) [376,377] X-ray crystallography [377,378,379], isothermal calorimetry (ITC) [379], UV-Vis and/or fluorescence spectroscopy [380].
T564 84794-84961 Sentence denotes The work of Goudreau et al. is an excellent example of combining NMR with another biophysical technique, in this case X-ray crystallography, for drug validation [378].
T565 84962-85135 Sentence denotes A series of benzodiazepine inhibitors of Human immunodeficiency virus 1 (HIV-1) was identified using an in vitro capsid assembly assay, and further characterized by 19F-NMR.
T566 85136-85332 Sentence denotes Analysis of the chemical shift perturbation and line broadening effect on the 19F-NMR spectra of the benzodiazepine inhibitors revealed the specificity and reversibility of the binding inhibitors.
T567 85333-85476 Sentence denotes The same set of 19F-NMR spectra were used to identify the N-terminal domain of the capsid as the binding site of the benzodiazepine inhibitors.
T568 85477-85640 Sentence denotes The specific amino acids involved in the binding of the benzodiazepine inhibitors were identified from the chemical shift perturbation of 1H,15N-TROSY NMR spectra.
T569 85641-85863 Sentence denotes Later, use of X-ray co-crystallography confirmed binding locations of the benzodiazepine inhibitors and their binding modes, which was useful for further development and optimization of the benzodiazepine inhibitors [378].
T570 85864-85998 Sentence denotes The work of Goudreau et al. therefore showed how NMR could be used as a co-validation technique with another biophysical method [378].
T571 85999-86146 Sentence denotes NMR can be also coupled with multiple biophysical techniques to validate a molecule’s ability to inhibit protein-protein interactions (PPIs) [367].
T572 86147-86452 Sentence denotes An example of the combination of NMR with SPR and X-ray crystallography can be found in the work of Fry et al., where the authors sought to understand how the nutlin molecule inhibits MDM2-p53, a protein-protein interaction that has been an important cancer therapy target for several years [381,382,383].
T573 86453-86697 Sentence denotes Fry et al. [377] gradually deconstructed RG7112, the first nutlin molecule to enter clinical trials [384], into 11 fragments so they could study the inhibitory effect of RG7112 on the MDM2-p53 interaction by SPR, NMR, and X-ray crystallography.
T574 86698-86867 Sentence denotes SPR was used to determine the Kd values of the RG7112 fragments and confirmed that RG7112 and some of its fragments do bind to MDM2, inhibiting the MDM2-p53 interaction.
T575 86868-86973 Sentence denotes 1H,15N-HSQC NMR chemical shift perturbation was also used to assess and verify binding identified by SPR.
T576 86974-87164 Sentence denotes Of the six fragments of RG7112 confirmed by 1H,15N-HSQC NMR as binding to MDM2, SPR showed binding for five of them; thus, the two separate techniques were in good agreement with each other.
T577 87165-87371 Sentence denotes The fragments of RG7112 that were confirmed to bind by both SPR and 1H,15N-HSQC NMR were further studied with X-ray crystallography, which can tell precisely where and how the molecules bind to the protein.
T578 87372-87589 Sentence denotes Using co-crystallization, Fry et al. were able to obtain structures for several of the verified binding fragments in complex with MDM2 and were able to visualize the binding of the fragments to the MDM2 protein [377].
T579 87590-87775 Sentence denotes NMR is obviously a powerful drug binding validation tool, but it becomes much more powerful when coupled with additional biophysical techniques, as seen in the work of Fry et al. [377].
T580 87776-87987 Sentence denotes Dias et al. [379] took a similar approach as Fry et al. [377] in that they took known inhibitors of a protein-protein interaction, and dissected them into individual fragments to assess a protein’s drug-ability.
T581 87988-88128 Sentence denotes The interaction studied was that between the proteins von Hippel–Lindau (VHL), and the alpha subunit of hypoxia-inducible factor 1 (HIF-1α).
T582 88129-88318 Sentence denotes Twelve compounds (known inhibitors and derived fragments) were developed using a crystal structure of HIF-1α peptide bound to the stable multiprotein complex pVHL-elongin C:elongin B (VCB).
T583 88319-88560 Sentence denotes Each of these compounds was screened using three separate NMR techniques, Saturation Transfer Difference (STD), Carr–Purcell–Meiboom–Gill (CPMG) relaxation experiments, and WaterLOGSY (to assess drug binding and to predict drug binding mode.
T584 88561-88804 Sentence denotes Each compound that was unambiguously detected (i.e., the molecule was identified as successfully binding by at least two of the three NMR methods of STD, CPMG, and WaterLOGSY) was subjected to further analysis by ITC and X-ray crystallography.
T585 88805-88972 Sentence denotes ITC was used to determine the dissociation constants of binding molecules, and X-ray crystallography was used to confirm the binding mode predicted by the NMR studies.
T586 88973-89222 Sentence denotes Generally speaking, the designed fragments had similar ligands efficacies compared to the parent molecules but had much higher dissociation constants (Kd values), meaning that the fragments bound less tightly than the original parent molecule [379].
T587 89223-89588 Sentence denotes With this example, it is possible to see the strength of using NMR as its own hit-validation tool (i.e., three different NMR techniques were used for screening compounds [379]), and yet, the follow-up of NMR studies with ITC and X-ray crystallography was useful in providing a basis for assessing the drug-ability of a protein-protein interaction [385,386,387,388].
T588 89589-89751 Sentence denotes Thus, it is clear to see that NMR is a prominent method of hit-validation in drug discovery research, especially in combination with other biophysical techniques.
T589 89753-89757 Sentence denotes 3.6.
T590 89758-89815 Sentence denotes Other Methods Used to Determine the Drug-Target Complexes
T591 89816-89970 Sentence denotes Substantial progress has been made in the NMR field over the past 5–10 years, and various methods were established to determine the drug-target complexes.
T592 89971-90112 Sentence denotes Most of them utilize either NOE or chemical shift perturbations (CSP) although in silico models/programs, using NMR-derivate data also exist.
T593 90114-90120 Sentence denotes 3.6.1.
T594 90121-90130 Sentence denotes DIRECTION
T595 90131-90318 Sentence denotes One of the methods called difference of inversion recovery rate with and without target irradiation (DIRECTION) is used to map pharmacophores and can be an alternative to STD experiments.
T596 90319-90475 Sentence denotes This method uses the difference between longitudinal relaxation rates of ligand protons with- and with-out irradiation of the protons of the target protein.
T597 90476-90570 Sentence denotes The DIRECTION approach, however cannot be used for slowly exchanging (strong binding) ligands.
T598 90571-90770 Sentence denotes The practical approach of this method was demonstrated on the experiment when analyzed the interactions between p38 MAPK (p38 a mitogen-activated protein kinase) and its inhibitor-SB203580 [389,390].
T599 90771-90957 Sentence denotes The results from this experiment showed that protons H1, H4, H5, and H6 of SB203580, are in close neighborhood with the protons of p38 MAPK when compared with H2, H3, and methyl protons.
T600 90958-91078 Sentence denotes It indicates that two aromatic rings (a pyridine ring and fluorophenyl ring) of SB203580 interact tightly with p38 MAPK.
T601 91079-91227 Sentence denotes The results were later confirmed with proton density map of each ligand’s proton, based on the crystal structure of SB203580–p38 MAPK complex [391].
T602 91228-91394 Sentence denotes Moreover, the same authors already created a new and improved protein–ligand docking method by combining the DIRECTION obtained NMR data with docking software. [392].
T603 91396-91402 Sentence denotes 3.6.2.
T604 91403-91407 Sentence denotes ILOE
T605 91408-91519 Sentence denotes A second method that can be used to map pharmacophores is called inter-ligand nuclear Overhauser effect (ILOE).
T606 91520-91745 Sentence denotes This 2D NMR experiment detects when two ligands bind simultaneously to adjacent sites on a protein surface although both of the ligands do not have to bind to the same binding pocket (opposite to INPHARMA, see above) [5,393].
T607 91746-91946 Sentence denotes A negative ligand−ligand NOE signal will be created when ligands bind in close proximity to each other whereas ligands that do not bind will show no NOEs, or at most very weak positive ones [372,394].
T608 91947-92040 Sentence denotes ILOE also enables determination of the ligand orientations with respect to one another [393].
T609 92041-92165 Sentence denotes As in the case of INPHARMA, ILOE can be utilized even in the absence of a 3D protein structure and used with large proteins.
T610 92166-92296 Sentence denotes Additionally, ILOE differs from INPHARMA in mixing times—for ILOE the mixing times are typically in the range of 600–800 ms [345].
T611 92297-92565 Sentence denotes Application of ILOE was first shown on glycolate+NAD+ in the presence of porcine heart lactatedehydrogenase, and by glucose-6-phosphate+NADPH in the presence of L. mesenteroides glucose-6-phosphatedehydrogenase and from that time it has been widely used [393,395,396].
T612 92567-92573 Sentence denotes 3.6.3.
T613 92574-92581 Sentence denotes SOS-NMR
T614 92582-92845 Sentence denotes A third method called structural information using Overhauser effects and selective labeling (SOS-NMR), relies of STD experiments performed on ligand complexes with different protein samples that have been fully deuterated excluding a specific type of amino acid.
T615 92846-93088 Sentence denotes In other words, the data obtained by SOS-NMR gives insight into the ligand-binding amino acid composition and when taken into consideration the 3D structure of targeted protein can be used to establish the structure of protein-ligand complex.
T616 93089-93266 Sentence denotes This approach has been demonstrated using two complexes—FKBP complexed to 2-(3′-pyridyl)-benzimidazole and MurA complexed to uridine diphosphateN-acetylglucosamine (UDP-GlcNAc).
T617 93267-93348 Sentence denotes The results showed that for FKBP and MurA, only four and three amino acids (FKBP:
T618 93349-93374 Sentence denotes Ile, Val, Leu, Met; MurA:
T619 93375-93493 Sentence denotes Trp, Phe, His) were needed to be selectively protonated in perdeuterated samples to establish the ligand-binding site.
T620 93494-93606 Sentence denotes Additionally, on average only 6 amino acids were required for accurate identification of ligand-binding surface.
T621 93607-93709 Sentence denotes According to authors SOS-NMR can greatly improve the early stages of the drug discovery process [397].
T622 93710-93837 Sentence denotes Moreover, combining SOS-NMR with other methods can even further increase chances for a positive outcome of an experiment [398].
T623 93839-93845 Sentence denotes 3.6.4.
T624 93846-93866 Sentence denotes Tert-butyl Labelling
T625 93867-93948 Sentence denotes A completely different approach to this topic was taken by Chen et al. [399,400].
T626 93949-94129 Sentence denotes Instead of using isotope labeling, Chen’s group decided to use a tert-butyl group contained within ligand-1 to obtain structural information about the protein-ligand complex [400].
T627 94130-94276 Sentence denotes The tert-butyl group formed an intense singlet in 1.0 to 1.5 ppm range thanks to rapid methyl rotation and methyl reorientation within that group.
T628 94277-94560 Sentence denotes When compared with the protein’s 1H-NMR signal, the tert-butyl signal tended to be much narrower and resulted in easy detection without the need for isotopic enrichment even in protein complexes of high molecular mass such as Bacillus stearothermophilus DnaB hexamer (320 kDa) [399].
T629 94561-94740 Sentence denotes Additionally, the tert-butyl group produces intense NOESY cross peaks that can be observed even in the situations where normally cross-peaks of the proteins are barely detectable.
T630 94741-94831 Sentence denotes This is partially because the signal corresponded to nine protons within tert-butyl group.
T631 94832-94946 Sentence denotes Those aspects enable measurements of pseudo-contact shifts generated by paramagnetic tags attached to the protein.
T632 94947-95011 Sentence denotes As a result, it allows positioning of the ligand on the protein.
T633 95012-95167 Sentence denotes An example of this approach, is dengue virus NS2B-NS3 protease from serotype 2 (referred as DENpro) in complexed with ligand containing a tert-butyl group.
T634 95168-95288 Sentence denotes The result of this experiment showed NOEs between the tert-butyl group of ligand-1 and residue Val155 from DENpro [400].
T635 95290-95296 Sentence denotes 3.6.5.
T636 95297-95303 Sentence denotes SALMON
T637 95304-95481 Sentence denotes Solvent accessibility, ligand binding, and mapping of ligand orientation by NMR spectroscopy (SALMON) is another method based on the data obtained via nuclear Overhauser effect.
T638 95482-95740 Sentence denotes This method utilizes WaterLOGSY [401] to probe for solvent accessibility to the ligand and determine the orientation of the ligand by analyzing signal changes in WaterLOGSY spectra (positive signal from unbound ligand vs. negative for protein-bound ligands).
T639 95741-95932 Sentence denotes This method was first used to determine the orientation of prodrug called tretazicar ((5-(aziridin-1-yl)-2,4-dinitrobenzamide) known as CB1954 in NQO2 (quinone oxidoreductase 2) binding site.
T640 95933-96148 Sentence denotes Previous attempts had been made to obtain the orientation of tretazicar bounded to NQO2, however the results obtained from X-ray crystallography were inconclusive as two orientations of tretazicar could be possible.
T641 96149-96375 Sentence denotes The information obtained via SALMON showed that the side chain of asparagine at position 161 formed a hydrogen bond with 2-nitrogroup of tretazicar, and that the aziridine moiety of tretazicar pointed toward the solvent [401].
T642 96377-96383 Sentence denotes 3.6.6.
T643 96384-96399 Sentence denotes LOGSY Titration
T644 96400-96518 Sentence denotes Another variant of WaterLOGSY method called LOGSY utilizes the titration slopes as a measure of solvent accessibility.
T645 96519-96601 Sentence denotes The titration slopes are created by a constant increase of protein concentrations.
T646 96602-96746 Sentence denotes This method also provides more insight into the process of ligand solvation by checking the influence of protein concentration onto the process.
T647 96747-96908 Sentence denotes This approach was used on the bromodomain 1 of protein 4 (Brd4-BD1) by mapping epitopes of two ligands interacting with Brd4-BD1 and predicting ligands position.
T648 96909-97029 Sentence denotes The results showed that the triazolopyridazine moiety of both ligands was implanted into the binding pocket of the Brd4.
T649 97030-97206 Sentence denotes Additionally, the results from LOGSY titration showed that methyl-group 1 of ligand 1, aromatic proton 8 of ligand 2 and aromatic proton 8 of ligand 1 exhibit strong water NOE.
T650 97207-97436 Sentence denotes This information enabled researchers to utilize a chemical replacement strategy (substitute bound water molecules by suitable functional groups) for aromatic proton 8 in a series of ligands containing the triazolopyridazine ring.
T651 97437-97575 Sentence denotes Those protons were replaced with an amino or aminomethyl groups and as a result, the binding affinity of those ligands increased 100-fold.
T652 97576-97897 Sentence denotes Finally, the results obtained from X-ray crystallography for ligands with such modifications allowed to find the binding mode of the triazolopyridazine ring of ligand 1 (with methyl group pointing internally) and the substituted amino group was found to create hydrogen bond to the side chain of Asn140 of Brd4-BD1 [402].
T653 97899-97905 Sentence denotes 3.6.7.
T654 97906-97961 Sentence denotes Nuclear Magnetic Resonance Molecular Replacement (NMR2)
T655 97962-98169 Sentence denotes The most recent approach called Nuclear Magnetic Resonance Molecular Replacement (NMR2) utilizes spatial data obtained through solution-state NMR in order to locate the binding pocket of a complex structure.
T656 98170-98340 Sentence denotes For that, it uses a receptor model, e.g., a X-ray structure of a homolog, to conduct an analysis and at the same time excluding the need for protein resonance assignment.
T657 98341-98410 Sentence denotes To conduct an experiment using such an approach requires a few steps.
T658 98411-98505 Sentence denotes First, either the protein or ligand used in the complex must be uniformly 13C and 15N labeled.
T659 98506-98595 Sentence denotes Then, an experiment to assign the ligand is needed such as 2D 13C,1H-HMQC or 13C,1H-HMBC.
T660 98596-98759 Sentence denotes The next step is the evaluation of ligand intra- and ligand–protein intermolecular distances through NOE cross peaks obtained from F1-15N,13C-filtered 1H,1H-NOESY.
T661 98760-98938 Sentence denotes Lastly, choosing a proper input structure is required which can be either X-ray or NMR structures in apo form, with another bound ligand, or a homolog to the protein of interest.
T662 98939-99108 Sentence denotes Then the NMR2 program analyzes for all possible partial assignments (such as methyl groups of a protein) and calculates the complex structures for all options [403,404].
T663 99109-99241 Sentence denotes This method was already successfully used to resolve complex structures in case of slow and fast exchange ligands [403,404,405,406].
T664 99243-99249 Sentence denotes 3.6.8.
T665 99250-99255 Sentence denotes HECSP
T666 99256-99373 Sentence denotes In silico methods combined with NMR derived information can also be used to determine accurate drug-target complexes.
T667 99374-99509 Sentence denotes 1H empirical chemical shift perturbation (HECSP) is an empirical model that is based on chemical shift perturbation (CSP) of a protein.
T668 99510-99653 Sentence denotes CSP represents the change in chemical shifts in a protein due to alteration of its chemical environment (which can happen upon ligand binding).
T669 99654-99813 Sentence denotes The CSP of a target protein is obtained by a series of 2D HSQC experiments with a set of ligand titrations involving samples that contain 15N-labelled protein.
T670 99814-99891 Sentence denotes The calculation of 1H-CSPs inside the protein are based on four contributors:
T671 99892-99981 Sentence denotes 1) ring current, 2) electric field, 3) hydrogen bonding, and last 4) magnetic anisotropy.
T672 99982-100182 Sentence denotes To show the value of the HECSP model two CSP examples were used: apo-neocarzinostatin (apoNCS)-naphthoate ester complex, and human intestinal fatty acid binding protein (hIFABP)-ketorolac-ANS complex.
T673 100183-100374 Sentence denotes The results from the experiment showed that HECSP model can distinguish native ligand from decoys and more clearly define protein-ligand complex structures with NMR derived information [407].
T674 100376-100382 Sentence denotes 3.6.9.
T675 100383-100390 Sentence denotes SAMPLEX
T676 100391-100572 Sentence denotes Another program that can utilize CSP called Smoothed Automatic Mapping of Protein from Listed Extremes (SAMPLEX) can help to determine the interaction surface of proteins complexes.
T677 100573-100730 Sentence denotes SAMPLEX takes the chemical shifts of the protein of interests in both the free and bound state and corresponding 3D structure of a protein in the free state.
T678 100731-100914 Sentence denotes The programs returns a confidence value for each residue to be in a perturbed or unperturbed state (0.05 as being in a perturbed state, −0.05 as remaining in their unperturbed state).
T679 100915-101063 Sentence denotes This approach was tested on five examples, one of which was Subtilisin BPN’ (serine protease) complexed with its inhibitor–chymotrypsin inhibitor 2.
T680 101064-101202 Sentence denotes The results showed that residue 2, and residues 56–62 of chymotrypsin inhibitor-2 were perturbed and residue 63 was in an ambiguous state.
T681 101203-101309 Sentence denotes To compare, the X-ray crystallography data showed residues 50 and 54–61 to be involved in the interaction.
T682 101310-101486 Sentence denotes For subtilisin BPN’ the program predicted residues 33, 97, 99–109, 126-128, 141, 154–156, 167–171 and 218–219 to perturbed and residues 65, 98 and 220 to be in ambiguous state.
T683 101487-101642 Sentence denotes That information was also confronted with the X-ray crystallography data which shown residues 99–104, 125–128, 154–157, 167, 218–221 to be perturbed [408].
T684 101644-101646 Sentence denotes 4.
T685 101647-101669 Sentence denotes In-Cell NMR Approaches
T686 101670-101849 Sentence denotes The interactions between targets (proteins) and ligands (small molecules) can be analyzed independently of the biological systems by using ‘cell-based’ NMR drug design approaches.
T687 101850-102001 Sentence denotes Three basic approaches [409] are as follows: (1) Compound-detected in-cell NMR, (2) Target-detected in-cell NMR, and (3) Reporter-detected in-cell NMR.
T688 102002-102186 Sentence denotes These methods, with the exception of compound detected in-cell NMR, differ according to the isotopically labeled structure (protein, cell structure, etc.), which enables NMR detection.
T689 102187-102259 Sentence denotes A cartoon representation of each of these methods is given in Figure 13.
T690 102261-102265 Sentence denotes 4.1.
T691 102266-102295 Sentence denotes Compound-Detected In-Cell NMR
T692 102296-102440 Sentence denotes STD NMR is a technique that lies within the compound-detected in-cell NMR method but does not require isotope-labelling of the studied compound.
T693 102441-102534 Sentence denotes However isotopic labelling of the compound may be used to enhance the quality of the spectra.
T694 102536-102540 Sentence denotes 4.2.
T695 102541-102568 Sentence denotes Target-Detected In-Cell NMR
T696 102569-102684 Sentence denotes In the target-detected in-cell NMR only the target of interest is isotopically labeled (i.e., 15N labeled protein).
T697 102685-102827 Sentence denotes For instance, target proteins can be isotopically labeled during cell growth in isotopically enriched (13C, 15N, or both 15N/13C) media [410].
T698 102828-102894 Sentence denotes The cell type and the labeling method may vary across experiments.
T699 102895-103082 Sentence denotes Different cell types, including bacteria [411], oocytes [412], yeast cells [413], mammalian cells [414], HeLa cells [415] and even insect cells [416] have been reported in the literature.
T700 103083-103217 Sentence denotes The fact that in-cell NMR applies to more than one cell type testifies of the versatility and potential application of this technique.
T701 103218-103336 Sentence denotes In terms of labeling, 15N is one of the most commonly used approaches [417] when the targets of interest are proteins.
T702 103337-103434 Sentence denotes Recently, 19F labeling has been reported as a useful probe for protein-ligand interactions [418].
T703 103435-103536 Sentence denotes It was shown that 19F can reveal information about the dynamics of protein-ligand interactions [419].
T704 103537-103738 Sentence denotes Methyl groups [420] have also been used as probes for proteins and complexes in vivo [420], proving that labeling specific chemical groups instead of the entire biomolecule (i.e., protein) is feasible.
T705 103740-103744 Sentence denotes 4.3.
T706 103745-103774 Sentence denotes Reporter-Detected In-Cell NMR
T707 103775-103890 Sentence denotes In-cell NMR extends beyond proteins, and has been applied successfully to DNA [93,421] and RNA molecules [422,423].
T708 103891-103972 Sentence denotes Telomeric repeats have also been studied using target detected in-cell NMR [424].
T709 103973-104162 Sentence denotes The reporter-detected in-cell NMR technique isotopically labels neither the ligand nor the target, but rather a receptor that indirectly measures the effects of ligand-target binding [409].
T710 104163-104223 Sentence denotes The “reporter” varies according to the experimental context.
T711 104224-104375 Sentence denotes For instance, Dose et al. [425] used acetylation- and deacetylation-based assays to monitor the activity of histone deacetylase and acetyl-transferase.
T712 104376-104498 Sentence denotes Thongwichian et al. [426] used peptide-based reporters to identify active kinases and phosphatases in cellular conditions.
T713 104499-104664 Sentence denotes Lastly, Doura et al. [427] designed a 19F probe that operates in biological conditions in order to study the adherence and dynamics of proteins found in human blood.
T714 104666-104694 Sentence denotes 4.4. “In-Virus” NMR Strategy
T715 104695-104910 Sentence denotes In many viruses and phages, scaffolding proteins (SPs) are required to ensure the correct organization of coat proteins (CPs) and other minor capsid proteins into a precursor structure, called a procapsid [428,429].
T716 104911-105089 Sentence denotes Although SPs are critical for viral assembly and therefore potential therapeutic targets their structural properties (with only a few exceptions [430,431]) are poorly understood.
T717 105090-105240 Sentence denotes The size limitation of NMR can be used advantageously as a filter to identify disordered segments even in very large supramolecular protein complexes.
T718 105241-105383 Sentence denotes In this way, NMR can provide a unique perspective on the dynamic and disordered elements of macromolecules not accessible by other techniques.
T719 105384-105793 Sentence denotes The procapsid encapsulation experiments described by Whitehead et al. [432] were conceptually analogous to in-cell NMR experiments [433,434,435] in which signals from small proteins, or flexible segments of proteins, can be observed when they are incorporated inside living cells, as long as the isotope-labeled proteins of interest do not interact strongly with other large cellular components [433,434,435].
T720 105794-106065 Sentence denotes The so called ‘‘in-virus’’ NMR strategy applied by Whitehead et al. [432] could be more generally used to study the dynamic properties of macromolecules encapsulated into virus particles, including cargo molecules encased in viral capsids for nanotechnology applications.
T721 106066-106217 Sentence denotes Additionally, such studies could assess the level of interaction of cargo molecules with the virus and probe the release properties of cargo NMR [432].
T722 106219-106221 Sentence denotes 5.
T723 106222-106235 Sentence denotes Final Remarks
T724 106236-106337 Sentence denotes As we have attempted to emphasize and demonstrate, NMR has a powerful and unique role in drug design.
T725 106338-106493 Sentence denotes NMR provides detailed structural information about a molecule along with kinetic information over extended time periods, i.e., not just a snapshot [24,25].
T726 106494-106673 Sentence denotes Moreover, NMR is quantitative and highly reproducible, allowing applications in diverse fields such as relaxometry, combinatorial chemistry, fluxomics, and targeted analysis [91].
T727 106674-106818 Sentence denotes NMR can be combined with other analytical techniques, such as mass spectrometry “in tandem” analysis of the molecules of interest [436,437,438].
T728 106819-107012 Sentence denotes 1H 1D-NMR is used particularly in the analysis of metabolites, while the strength and intensity of the recorded signals is directly proportional to the concentration of the sample [44,439,440].
T729 107013-107100 Sentence denotes 1H 1D-NMR can also be used to follow “real-time” analysis of different molecules [441].
T730 107101-107307 Sentence denotes In the 1D 1H-NMR experiment, there are no polarization transfer techniques required (the 1H atom is already highly sensitive) and covers a spread of interesting nuclei in the molecule(s) being studied [91].
T731 107308-107486 Sentence denotes Assuming that the sample can be stored stably for extended periods of time, the non-destructive nature of NMR permits the re-use on the sample for different experiments [50,442].
T732 107487-107595 Sentence denotes Aiding in the reproducibility of NMR [91], sample-recycling offers a significant advantage of NMR [443,444].
T733 107596-107723 Sentence denotes While always important in drug design, sensitivity and resolution of NMR are two major factors that need special consideration.
T734 107724-107866 Sentence denotes Since both factors improve with increasing magnetic field strength, we have seen a spike in the demand for ultra-high-field NMR spectrometers.
T735 107867-108226 Sentence denotes Recently, 28.2 T (i.e., 1.2 GHz for 1H) magnets have become commercially available, and with recent advances in magnet technology, such as liquid helium recycling and magnetic field shielding [91], NMR has begun to offer far better resolution and higher sensitivity while reducing the substantial costs of maintaining the instruments compared to past decades.
T736 108227-108513 Sentence denotes Other steps have been taken to enhance the sensitivity of NMR including: the development of cryoprobes increasing the signal to noise ratio 3 to 4 times, and micro-coil probes that not only increased sensitivity but also reduced the amount of sample required for the measurements [445].
T737 108514-108641 Sentence denotes From another perspective, one can further optimize the process of obtaining spectra by using different methods of measurements.
T738 108642-108823 Sentence denotes One of these, called SOFAST, helps to reduce the delay between scans resulting in lowering acquisition time for 2D experiments such as HMQC utilizing 1H,15N or 1H,13C [117,446,447].
T739 108824-109105 Sentence denotes The basic principle of this method is to use selective 1H pulses that will excite only a small portion of the available nuclei pool, while the unperturbed spins provide a magnetization “heat sink” thus improving the spin-lattice relaxation (T1) rate via dipolar interactions [446].
T740 109106-109204 Sentence denotes These methods can be highly efficient when studying drug binding and molecular interactions [117].
T741 109205-109360 Sentence denotes Another method, called ultrafast 2D NMR, enables obtaining a 2D spectra within a single scan but with the associated cost of reduced sensitivity [117,448].
T742 109361-109571 Sentence denotes The principle of this method is to divide the sample into n number of fractions, and apply the appropriate incremental aspect to each fraction, while recording them all simultaneously within the one scan [448].
T743 109572-109696 Sentence denotes This method has been applied to many metabolomic studies [177,447,449] as well as in the analysis of natural products [450].
T744 109697-109800 Sentence denotes The difficulty is that the effective concentration of the sample is lowered by the fractionation level.
T745 109801-109905 Sentence denotes The more slices the sample is split into, the greater the reduction of combined signal that is obtained.
T746 109906-110080 Sentence denotes Lastly, a method termed non-uniform sampling (NUS) may provide an advantage by reducing the total time for measurement while maintaining the same resolution of spectra [117].
T747 110081-110182 Sentence denotes NUS effectively skips over parts of the total dataset, collecting only around 20 to 30% of the total.
T748 110183-110333 Sentence denotes Usually sections containing higher concentrations of signal (over noise) are emphasized in the selection scheme, known as non-linear data acquisition.
T749 110334-110669 Sentence denotes These methods reconstruct the complete data subset by applying various algorithms such as multidimensional decomposition (MDD), which essentially separates the sets of multidimensional data into one dimensional problems that are much easier to solve given the common process of signal overlapping in multidimensional NMR spectra [117].
T750 110670-110899 Sentence denotes Other algorithms such as compressed sensing (CS), Maximum entropy method (Max Ent) and Iterative soft threshold (IST) each have their own advantages but all focus on decreasing the time needed for collection of spectra [117,451].
T751 110900-110967 Sentence denotes The cost is in signal to noise, as no gain is ever absolutely free.
T752 110968-111150 Sentence denotes The inherent advantages of NMR do not eliminate the disadvantages (Table 3), which are namely being limited for some nuclei, and inherent insensitivity for many types of experiments.
T753 111151-111276 Sentence denotes NMR can provide high quality resolution and sensitivity for some experiments [91,452] but the application can be challenging.
T754 111277-111596 Sentence denotes When the experiments become multidimensional, there is often a tradeoff between the improved higher resolution and/or the resulting sensitivity and/or the amount of time an experiment takes, i.e., high-quality spectra for multidimensional experiments take much longer than their simple 1D counterparts [117] (Scheme 2).
T755 111597-111721 Sentence denotes One must always choose between resolution, sensitivity, and the amount time; as you can only ever have two out of the three.
T756 111722-111907 Sentence denotes Unfortunately, in the real world, when working with NMR spectroscopy, we are mainly forced to choose between high or low precision data (Scheme 2) with fixed available instrument times.
T757 111908-112001 Sentence denotes Scheme 2 can be useful, when choosing NMR technique and/or method/approaches in drug studies.
T758 112002-112274 Sentence denotes It shows the general representation of different NMR techniques and method/approaches in cost-time matrix, bearing in mind that the exact position in the matrix can be influenced by the environmental conditions, pulse sequence and sample preparation (e.g., concentration).
T759 112275-112375 Sentence denotes Regarding, NMR methods/approaches, the exact position depends on the choice of proper NMR technique.
T760 112376-112475 Sentence denotes For the purposes of Scheme 2, the 2D techniques were chosen as described in the practical examples.
T761 112476-112658 Sentence denotes Nevertheless, with relatively short times and at low cost, we can acquire numerous data sets and therefore the low precision can be partially compensated for by statistical analysis.
T762 112659-112858 Sentence denotes Fortunately, significant efforts have been undertaken to reduce the amount of time it takes to record multidimensional spectra, especially for 2D NMR, and still obtain high quality spectra (Table 3).
T763 112859-112944 Sentence denotes Novel pulse sequences have been developed to decouple nuclei in Pure-shift NMR [117].
T764 112945-113075 Sentence denotes Dynamic Nuclear Polarization (DNP) can induce hyper-polarization in atoms (13C, 15N) with an inherently low sensitivity [453,454].
T765 113076-113279 Sentence denotes Parahydrogen-Induced Polarization (PHIP) and Signal Amplification by Reversible Exchange (SABRE) are other polarization techniques used to increase the sensitivity of inherently insensitive nuclei [455].
T766 113281-113283 Sentence denotes 6.
T767 113284-113295 Sentence denotes Conclusions
T768 113296-113401 Sentence denotes NMR has become a “gold standard” method in drug design due to its speed, simplicity, and reproducibility.
T769 113402-113530 Sentence denotes The standardized ppm scale allows one to compare all NMR results and gather them in databases for the common use of researchers.
T770 113531-113723 Sentence denotes Although sample labeling was limiting in the beginning, it has now become a strength of NMR that permits the observation of big molecules and/or biomolecular processes “through the door lock”.
T771 113724-113863 Sentence denotes NMR is the only analytical technique that permits qualitative and quantitative analysis without previous sample purification or separation.
T772 113864-114006 Sentence denotes High precision NMR data still requires long experiment times and has elevated costs; however, these will no doubt be alleviated in the future.