LitCovid-sentences  

PMC:7247521 / 13869-40378 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T85 0-9 Sentence denotes 3 Result
T86 11-77 Sentence denotes 3.1 Prediction of active components and potential targets of QFPD
T87 78-215 Sentence denotes Firstly, the DL ≥ 0.18 and OB ≥ 30 %.s were set as the standard to screen the chemical components obtained through online database TCMSP.
T88 216-435 Sentence denotes Specifically, a total of 175 effective components of QFPD were screened from the TCM database, including 82 species of MSXG, 35 species of SGMH, 105 species of XCH, 21 species of WLS and 32 species of Others (Table 1 ).
T89 436-658 Sentence denotes Among these effective components, 89 (50.86 %) components exited in more than two formulae; CID5280343 and CID5280794 were owned by MXSG, Others, SGMH and XCH; CID12303645 was owned by MXSG, Others, WLS and XCH (Fig. 1 A).
T90 659-859 Sentence denotes Secondly, a total of 300 targets of QFPD were screened from the BATMAN-TCM database, including 192 targets of MSXG, 201 targets of SGMH, 221 targets of XCH, 96 targets of WLS and 99 targets of Others.
T91 860-932 Sentence denotes Among these proteins, 21 (7%) targets exited in five formulae (Fig. 1B).
T92 933-970 Sentence denotes Table 1 Effective components of QFPD.
T93 971-992 Sentence denotes Formula N PubChem_Cid
T94 993-1888 Sentence denotes MSXG 82 CID10090416,CID10542808,CID10881804,CID11267805,CID114829,CID11558452,CID11602329,CID11975273,CID120074,CID12303645,CID124049,CID124052,CID13965473,CID14604077,CID14604078,CID14604081,CID15228663,CID15380912,CID162412,CID177149,CID193679,CID197678,CID23724664,CID25015742,CID268208,CID336327,CID354368,CID3764,CID439246,CID440833,CID442411,CID44257530,CID480774,CID480780,CID480787,CID480859,CID480873,CID49856081,CID503731,CID503737,CID5280343,CID5280378,CID5280448,CID5280544,CID5280794,CID5280863,CID5281619,CID5281654,CID5281789,CID5282768,CID5282805,CID5312521,CID5316900,CID5317300,CID5317478,CID5317479,CID5317480,CID5317652,CID5317768,CID5317777,CID5318437,CID5318585,CID5318679,CID5318869,CID5318998,CID5318999,CID5319013,CID5320083,CID5460988,CID5481234,CID5481948,CID5481949,CID5997,CID636883,CID637112,CID64971,CID6918970,CID73205,CID928837,CID9927807,CID15840593,CID15228662
T95 1889-2375 Sentence denotes SGMH 35 CID1135,CID1174,CID3026,CID5789,CID6782,CID6998,CID8437,CID8679,CID13625,CID117158,CID159225,CID185,CID10019512,CID11438306,CID11869417,CID11870462,CID12315507,CID162350,CID16726037,CID222284,CID389888,CID3902,CID440833,CID5280343,CID5280445,CID5280544,CID5280794,CID5280863,CID5281331,CID5281605,CID5281616,CID5281628,CID5281654,CID5281779,CID5282768,CID5315890,CID5316876,CID5320945,CID5484202,CID5488781,CID5491637,CID64959,CID64982,CID676152,CID71307581,CID72307,CID13688752
T96 2376-3516 Sentence denotes XCH 105 CID10090416,CID10542808,CID10881804,CID11267805,CID11438306,CID114829,CID11558452,CID11602329,CID117443,CID12303645,CID124049,CID124052,CID124211,CID13965473,CID14135323,CID14604077,CID14604078,CID14604081,CID15228662,CID15228663,CID15380912,CID156992,CID158311,CID15840593,CID159029,CID161271,CID162412,CID177149,CID185034,CID193679,CID197678,CID222284,CID23724664,CID25015742,CID25721350,CID268208,CID336327,CID354368,CID373261,CID3764,CID389001,CID389888,CID439246,CID442411,CID44257530,CID44258628,CID480774,CID480780,CID480787,CID480859,CID480873,CID49856081,CID503731,CID503737,CID5280343,CID5280378,CID5280442,CID5280448,CID5280794,CID5280863,CID5281605,CID5281619,CID5281654,CID5281674,CID5281703,CID5281789,CID5282768,CID5312521,CID5316900,CID5317300,CID5317478,CID5317479,CID5317480,CID5317652,CID5317768,CID5317777,CID5318437,CID5318585,CID5318679,CID5318869,CID5318998,CID5318999,CID5319013,CID5319042,CID5319252,CID5320083,CID5320315,CID5320399,CID5321865,CID5322059,CID5322078,CID5460988,CID5481234,CID5481948,CID5481949,CID5484202,CID636883,CID637112,CID64959,CID64971,CID64982,CID73205,CID821279,CID928837,CID9927807
T97 3517-3757 Sentence denotes WLS 21 CID10181133,CID10743008,CID12303645,CID14036811,CID15225964,CID15226717,CID15976101,CID182232,CID222284,CID44575602,CID5283628,CID5471851,CID5471852,CID56668247,CID6436630,CID712316,CID73402,CID9064,CID9805290,CID14448075,CID14236575
T98 3758-4102 Sentence denotes Others 32 CID10212,CID11824478,CID122159,CID12303645,CID14057197,CID145659,CID17897,CID33934,CID373261,CID40429858,CID42607889,CID439246,CID442834,CID443024,CID5280343,CID5280445,CID5280794,CID5281326,CID5281617,CID5281781,CID5319406,CID5320621,CID5495928,CID5997,CID631170,CID632135,CID676152,CID712316,CID72344,CID79730,CID1149877,CID45359875
T99 4103-4174 Sentence denotes Fig. 1 Venn diagram of the five formulae’ active compounds and targets.
T100 4175-4200 Sentence denotes A: compounds, B: targets.
T101 4202-4265 Sentence denotes 3.2 Functional and pathway enrichment analyses of QFPD targets
T102 4266-4538 Sentence denotes As shown in Fig. 2 , the 11 enriched GO terms of the targets in all five formulae were found, such as oxidoreductase activity, lipid metabolic process, lipid binding, small molecule metabolic process, homeostatic process, signal transducer activity and cell proliferation.
T103 4539-4909 Sentence denotes Furthermore, the results of pathway enrichment analysis showed that the 7 KEGG pathways were significantly related to more than 4 formula groups, including dteroid biosynthesis, adipocytokine signaling pathway, neuroactive ligand-receptor interaction, steroid hormone biosynthesis, PPAR signaling pathway, arginine and proline metabolism and ABC transporters (Fig. 3 A).
T104 4910-5140 Sentence denotes In addition, TTD analysis showed that the 8 diseases were significantly association with more than 3 formula groups, such as acne, Behcet'S disease, benign prostate hyperplasia, intrahepatic cholestasis and brain injury (Fig. 3B).
T105 5141-5250 Sentence denotes However, the five formulae contained their specific (MSXG, SGMH, XCH, WLS and Others) GO, KEGG and TTD terms.
T106 5251-5644 Sentence denotes For example, neurological system process and beta-Alanine metabolism terms were specific for MXSG; membrane organization and parasitic infections of the eye terms for SGMH; circadian rhythm and hypertension terms for XCH; nucleic acid binding transcription factor activity, ovarian steroidogenesis and chronic inflammatory diseases terms for WLS; fat digestion and absorption terms for Others.
T107 5645-5713 Sentence denotes Fig. 2 Bubble plot of the GO analysis of the five formulae’ targets.
T108 5714-5788 Sentence denotes Fig. 3 Bubble plot of the KEGG/TTD analysis of the five formulae’ targets.
T109 5789-5805 Sentence denotes A: KEGG, B: TTD.
T110 5806-6011 Sentence denotes In the prediction of miRNAs in QFPD targets, MIR-183 and MIR-130A/B/301 were the highest linking terms to bind the five formulae targets and formulae Others was the highest group to bind miRNAs (Fig. 4 A).
T111 6012-6139 Sentence denotes In addition, kinase prediction revealed CDK7 were significantly enriched in formulae MSXG, SGMH, XCH, WLS and Others (Fig. 4B).
T112 6140-6299 Sentence denotes Finally, TF analysis showed that LXR was the highest linking TF to bind the four formulae targets and formulae WLS was the highest group to bind TFs (Fig. 4C).
T113 6300-6385 Sentence denotes Fig. 4 The miRNA, kinase and TF analysis of the five formulae’ targets by WebGestalt.
T114 6386-6495 Sentence denotes Chord plot showing the five formulae’ targets present in the represented enriched miRNA, kinase and TF terms.
T115 6496-6601 Sentence denotes Outer ring shows miRNA/kinase/TF term and log2 enrichment ratio (left) or five formulae grouping (right).
T116 6602-6659 Sentence denotes Chords connect miRNA/kinase/TF term with formulae groups.
T117 6660-6687 Sentence denotes A: miRNA, B: kinase, C: TF.
T118 6689-6748 Sentence denotes 3.3 Construction of PPI network and MCODE modules analysis
T119 6749-6914 Sentence denotes To further explore the functional relationship among five formulae, PPI networks were constructed through Metascape, and visual composition carried out by Cytoscape.
T120 6915-7120 Sentence denotes Firstly, the potential 192 target genes of MXSG were analyzed by PPI network, and the results showed that there were 144 nodes and 510 edges, which represented the interaction between protein and function.
T121 7121-7265 Sentence denotes The MXSG PPI network function module was confirmed by the MCODE plug-in and a list of the corresponding meaningful modules presented (Fig. 5 A).
T122 7266-7294 Sentence denotes 3 modules scores were > 2.5.
T123 7295-7311 Sentence denotes Module 1 (score:
T124 7312-7387 Sentence denotes 5.769) consisted of 13 nodes and the seed gene was COX7A1; Module 2 (score:
T125 7388-7464 Sentence denotes 4.429) consisted of 14 nodes and the seed gene was ALDH1A1; module 3 (score:
T126 7465-7519 Sentence denotes 5.0) consisted of 11 nodes and the seed gene was CNR2.
T127 7520-7719 Sentence denotes KEGG pathway enrichment analysis showed that MXSG modules were enriched in neuroactive ligand-receptor interaction, calcium signaling pathway, inflammatory mediator regulation of TRP channels, et.al.
T128 7720-7758 Sentence denotes Fig. 5 KEGG analysis of MCODE modules.
T129 7759-7901 Sentence denotes MCODE analysis was performed after the construction of the five formulae’ targets PPI; then, KEGG analysis was conducted on the MCODE modules.
T130 7902-7913 Sentence denotes A: MXSG, B:
T131 7914-7946 Sentence denotes Others, C: WLS, D: SGMH, E: XCH.
T132 7947-8089 Sentence denotes Secondly, the potential 99 target genes of Others were analyzed by PPI network, and the results showed that there were 77 nodes and 194 edges.
T133 8090-8131 Sentence denotes Only 1 module score were > 2.5 (Fig. 5B).
T134 8132-8148 Sentence denotes Module 1 (score:
T135 8149-8207 Sentence denotes 5.769) consisted of 13 nodes and the seed gene was COX7A1.
T136 8208-8368 Sentence denotes KEGG pathway enrichment analysis showed that Others modules were enriched in huntington's disease, glycolysis / gluconeogenesis, Notch signaling pathway, et.al.
T137 8369-8507 Sentence denotes Thirdly, the potential 96 target genes of WLS were analyzed by PPI network, and the results showed that there were 60 nodes and 143 edges.
T138 8508-8550 Sentence denotes Only 1 modules score were > 2.5 (Fig. 5C).
T139 8551-8567 Sentence denotes Module 1 (score:
T140 8568-8624 Sentence denotes 2.706) consisted of 17 nodes and the seed gene was CNR2.
T141 8625-8814 Sentence denotes KEGG pathway enrichment analysis showed that WLS modules were enriched in thyroid hormone signaling pathway, adipocytokine signaling pathway, neuroactive ligand-receptor interaction, et.al.
T142 8815-8957 Sentence denotes Fourthly, the potential 201 target genes of SGMH were analyzed by PPI network, and the results showed that there were 153 nodes and 505 edges.
T143 8958-8996 Sentence denotes 3 modules scores were > 2.5 (Fig. 5D).
T144 8997-9013 Sentence denotes Module 1 (score:
T145 9014-9088 Sentence denotes 3.529) consisted of 17 nodes and the seed gene was ACSS1; Module 2 (score:
T146 9089-9159 Sentence denotes 4.5) consisted of 7 nodes and the seed gene was CNR2; module 3 (score:
T147 9160-9214 Sentence denotes 3.5) consisted of 8 nodes and the seed gene was PRKCG.
T148 9215-9376 Sentence denotes KEGG pathway enrichment analysis showed that SGMH modules were enriched in insulin resistance, adipocytokine signaling pathway, Th17 cell differentiation, et.al.
T149 9377-9517 Sentence denotes At last, the potential 221 target genes of XCH were analyzed by PPI network, and the results showed that there were 166 nodes and 643 edges.
T150 9518-9556 Sentence denotes 5 modules scores were > 2.5 (Fig. 5E).
T151 9557-9573 Sentence denotes Module 1 (score:
T152 9574-9649 Sentence denotes 5.769) consisted of 13 nodes and the seed gene was COX7A1; Module 2 (score:
T153 9650-9723 Sentence denotes 2.769) consisted of 13 nodes and the seed gene was RRM1; module 3 (score:
T154 9724-9795 Sentence denotes 5.5) consisted of 12 nodes and the seed gene was CNR2; module 4 (score:
T155 9796-9870 Sentence denotes 2.909) consisted of 11 nodes and the seed gene was ACSS1; module 5 (score:
T156 9871-9925 Sentence denotes 3.0) consisted of 7 nodes and the seed gene was FFAR1.
T157 9926-10102 Sentence denotes KEGG pathway enrichment analysis showed that XCH modules were enriched in calcium signaling pathway, cGMP-PKG signaling pathway, neuroactive ligand-receptor interaction, et.al.
T158 10104-10129 Sentence denotes 3.4 Network construction
T159 10130-10265 Sentence denotes After using the BATMAN-TCM, we constructed five ingredients-target-pathway-disease networks, including MSXG, SGMH, XCH, WLS and Others.
T160 10266-10482 Sentence denotes In order to emphasize the important network elements, we showed the networks that exhibit those targets with larger than 6, 5, 8, 7 and 4 linking compounds for MSXG, SGMH, XCH, WLS and Others, respectively (Fig. 6 ).
T161 10483-10833 Sentence denotes MSXG network contained 31 key components, 50 proteins and 17 pathways; SGMH network contained 15 key components, 20 proteins and 8 pathways; WLS network contained 18 key components, 9 proteins and 4 pathways; XCH network contained 32 key components, 15 proteins and 12 pathways; Others network contained 10 key components, 13 proteins and 3 pathways.
T162 10834-10951 Sentence denotes To find the potential drugs of formulae QFPD for COVID-19, a total of 67 hub components were used for ADMET analysis.
T163 10952-11004 Sentence denotes Fig. 6 The component-target-pathway-disease network.
T164 11005-11021 Sentence denotes Purple polygons:
T165 11022-11124 Sentence denotes PubChem ID of QFPD compounds; blue pentagrams: QFPD targets; yellow circles: KEGG pathway; red square:
T166 11125-11186 Sentence denotes Therapeutic Target Database (TTD) disease term, green square:
T167 11187-11243 Sentence denotes Online Mendelian Inheritance in Man (OMIN) disease term.
T168 11244-11280 Sentence denotes A: MXSG, B: SGMH, C: WLS, D: XCH, E:
T169 11281-11419 Sentence denotes Others. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
T170 11421-11466 Sentence denotes 3.5 ADMET evaluation of the 67 key compounds
T171 11467-11622 Sentence denotes Since in silico ADMET prediction can help early drug design and evaluation, ADMET properties of the 67 key compounds were predicted by SwissADME and pkCSM.
T172 11623-11817 Sentence denotes Chemical properties including molecular weight (MW), rotatable bonds count, H-bond acceptors and donors count, TPSA and leadlikeness violations were calculated by SwissADME and shown as Fig. 8A.
T173 11818-12037 Sentence denotes It is worth mentioning that 21 (31.34 %) compounds passed the stringent lead-like criteria (250 g/mol ≤ MW ≤ 350 g/mol, XLOGP ≤ 3.5 and rotatable bonds ≤ 7), which are excellent candidates for drug discovery (Fig. 7 A).
T174 12038-12163 Sentence denotes And these lead-likeness compounds were further predicted by pkCSM, with the exception of S3 (low gastrointestinal absorption)
T175 12164-12236 Sentence denotes Fig. 7 Chemical properties statistics of hub components in the formulae.
T176 12237-12239 Sentence denotes A:
T177 12240-12540 Sentence denotes Molecular weight, B: rotatable bond count, C: H-bond acceptors count, D: H-bond donors count, E: topological polar surface area (TPSA), F: leadlikeness violations, G: pharmacokinetic and toxicity evaluated parameters of 20 leadlikeness compounds by pkCSM; green = good, yellow = tolerable, red = bad.
T178 12541-12547 Sentence denotes Caco2:
T179 12548-12572 Sentence denotes Caco-2 Permeability,HIA:
T180 12573-12609 Sentence denotes Intestinal Absorption (Human), Skin:
T181 12610-12662 Sentence denotes Skin Permeability, VDss: volume of distribution, FU:
T182 12663-12693 Sentence denotes Fraction Unbound (Human), BBB:
T183 12694-12732 Sentence denotes Blood Brain Barrier permeability, CNS:
T184 12733-12772 Sentence denotes Central Nervous System permeability,TC:
T185 12773-12795 Sentence denotes Total Clearance, OCT2:
T186 12796-12858 Sentence denotes Renal Organic Cation Transporter 2, AMES: AMES toxicity, MTDD:
T187 12859-12933 Sentence denotes Maximum Tolerated Dose (Human), hERG I/II: hERG I and II Inhibitors, LD50:
T188 12934-12969 Sentence denotes Oral Rat Acute Toxicity (LD50), HT:
T189 12970-12989 Sentence denotes Hepatotoxicity, SS:
T190 12990-13013 Sentence denotes Skin Sensitisation, MT:
T191 13014-13161 Sentence denotes Minnow toxicity. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
T192 13162-13289 Sentence denotes Fig. 8 Schematic (3D and 2D) representation that molecular model of specific compounds of each formulae with COVID-19 proteins.
T193 13290-13447 Sentence denotes A: M3 and E protein [ion channel], B: M3 and nsp13 [Helicase NCB site], C: S1 and nsp13 [Helicase ADP site], D: S1 and PLpro, E: X2 and Mpro, F: O2 and Mpro.
T194 13448-13476 Sentence denotes M: MXSG, S: SGMH, X: XCH, O:
T195 13477-13484 Sentence denotes Others.
T196 13485-13664 Sentence denotes Regarding the absorption parameters, all 20 compounds (Table 2 ) presented a promising oral availability including the optimal Caco-2 cell permeability, HIA and skin permeability.
T197 13665-13896 Sentence denotes The drug distribution results showed that most of the compounds distributed in tissue (VDss> 0.45: tissue, VDss <−0.15: plasma) with good unbound fraction scores, thus becoming available to interact with the pharmacological target.
T198 13897-14019 Sentence denotes Only compound W5 and W11 were entirely unable to penetrate the blood-brain barrier (BBB) and central nervous system (CNS).
T199 14020-14154 Sentence denotes In addition, 15 compounds presented a good renal elimination and were not substrates of the renal organic cation transporter 2 (OCT2).
T200 14155-14410 Sentence denotes Finally, 14 compounds did not present any particular toxicity problems including AMES toxicity, maximum tolerated dose, hERG I inhibitor, hERG II inhibitor, oral rat acute toxicity (LD50), hepatotoxicity, skin sensitisation, and minnow toxicity (Fig. 7B).
T201 14411-14459 Sentence denotes Table 2 20 potential active compounds from QFPD.
T202 14460-14525 Sentence denotes Pubchem Molecular Name Structure Pubchem Molecular Name Structure
T203 14526-14586 Sentence denotes CID6918970 M3 ZINC5356864 CID10019512 S5 3-O-Methylviolanone
T204 14587-14632 Sentence denotes CID336327 M5 Medicarpin CID9064 W5 Cianidanol
T205 14633-14679 Sentence denotes CID14057197 O1 – CID182232 W11 (+)-Epicatechin
T206 14680-14736 Sentence denotes CID42607889 O2 Alysifolinone CID25721350 X1 ZINC13130930
T207 14737-14794 Sentence denotes CID3902 S1 letrozole CID14135323 X2 (2S)-dihydrobaicalein
T208 14795-14844 Sentence denotes CID821279 X4 ZINC338038 CID439246 MXO1 naringenin
T209 14845-14904 Sentence denotes CID440833 MS1 Leucocyanidol CID676152 SO1 SR-01,000,767,148
T210 14905-14967 Sentence denotes CID177149 MX16 (+)-Vestitol CID11438306 SX1 cyclo(L-Tyr-l-Phe)
T211 14968-15025 Sentence denotes CID114829 MX17 Liquiritigenin CID712316 WO1 (-)-taxifolin
T212 15026-15088 Sentence denotes CID928837 MX8 ZINC519174 CID373261 XO1 Eriodyctiol (flavanone)
T213 15089-15117 Sentence denotes M: MXSG, S: SGMH, X: XCH, O:
T214 15118-15125 Sentence denotes Others.
T215 15127-15149 Sentence denotes 3.6 Molecular docking
T216 15150-15675 Sentence denotes The application of COVID-19 docking server and Discovery Studio software elucidated the interactions between the 20 lead-likeness compounds (S1, W5, MX17, MX16, W11, M5, XO1, MXO1, SO1, WO1, X4, MX8, M3, S5, SX1, O1, X2, X1, O2, MS1) and the 10 nonstructural and 2 structural proteins (Mpro, PLpro, nsp12 [RdRp with RNA], nsp12 [RdRp without RNA], nsp13 [Helicase ADP site], nsp13 [Helicase NCB site], nsp14 [ExoN], nsp14 [N7-MTase], nsp15 [endoribonuclease], nsp16 [2′-O-MTase], N protein NCB site, E protein [ion channel]).
T217 15676-15730 Sentence denotes The docking scores were depicted in Table 3, Table 4 .
T218 15731-15875 Sentence denotes The smaller of docking score, the lower of energy would be required, which means the binding between the compounds and the targets are stronger.
T219 15876-15953 Sentence denotes There are 9 compounds presenting better bonding ability than other compounds.
T220 15954-16036 Sentence denotes Table 3 Docking score between specific ingredients of QFPD and 2019-nCov proteins.
T221 16037-16079 Sentence denotes Molecule M3 M5 S1 S5 W11 W5 X1 X2 X4 O1 O2
T222 16080-16148 Sentence denotes Main Protease −7.7 −7.3 −6.8 −6.9 −7.2 −7.5 −7.1 −7.9 −7.3 −7.1 −7.4
T223 16149-16220 Sentence denotes Papain-like protease −8.7 −8.5 −9.9 −7.7 −8 −8 −8.4 −8.7 −8.2 −8.6 −8.2
T224 16221-16289 Sentence denotes RdRp with RNA −8.4 −8.5 −8.5 −8.3 −9.1 −9.1 −8.4 −8.2 −8.2 −8.3 −8.6
T225 16290-16361 Sentence denotes RdRp without RNA −6.8 −6.8 −6.9 −6.8 −6.7 −6.9 −7.1 −7.2 −6.5 −7.3 −7.1
T226 16362-16430 Sentence denotes Helicase ADP site −6.3 −6.3 −7.3 −6.5 −6 −6 −6.3 −6.5 −6.2 −6.1 −6.5
T227 16431-16503 Sentence denotes Helicase NCB site −7.9 −6.9 −7.2 −7.1 −7.2 −7.2 −7.4 −7.5 −7.3 −7.4 −7.4
T228 16504-16570 Sentence denotes Nsp14(ExoN) −6.8 −6.6 −6.3 −6.4 −6.9 −6.8 −6.7 −6.9 −6.4 −6.6 −6.9
T229 16571-16639 Sentence denotes Nsp14(N7-MTase) −8.8 −8.1 −8.5 −7.5 −8.4 −8.4 −8.3 −8.5 −8 −8.3 −8.5
T230 16640-16718 Sentence denotes Nsp15(endoribonuclease) −6.6 −6.3 −6.3 −5.9 −6.2 −6.2 −6.2 −6.3 −6.2 −6.4 −6.4
T231 16719-16791 Sentence denotes Nsp16(2′-O-MTase) −7.5 −7.4 −7.5 −7.2 −8.2 −8.2 −7.7 −7.9 −7.7 −7.9 −8.4
T232 16792-16861 Sentence denotes N protein NCB site −7.6 −7.5 −7.8 −7.6 −7.6 −7.6 −8 −8 −7.5 −7.6 −7.6
T233 16862-16937 Sentence denotes E protein(ion channel) −8.1 −7 −7.8 −6.7 −6.4 −6.4 −7.2 −7.3 −7.2 −7.1 −6.8
T234 16938-16966 Sentence denotes M: MXSG, S: SGMH, X: XCH, O:
T235 16967-16974 Sentence denotes Others.
T236 16975-17066 Sentence denotes Table 4 Evaluation of the effect of QFPD on the robustness disturbance of COVID-19 network.
T237 17067-17110 Sentence denotes Topology MXSG SGMH XCH WLS Others BXTM YDBF
T238 17111-17156 Sentence denotes DTS 25.66 26.71 21.02 17.64 23.16 14.52 22.71
T239 17157-17201 Sentence denotes AC −4.63 −5.21 −3.02 −3.49 −5.38 −2.32 −3.78
T240 17202-17244 Sentence denotes APL 13.35 13.40 9.96 6.49 10.66 4.59 11.17
T241 17245-17290 Sentence denotes CoC −1.44 −1.64 −1.59 −1.30 −1.23 −1.15 −1.25
T242 17291-17336 Sentence denotes ClC −6.24 −6.46 −6.45 −6.36 −5.88 −6.46 −6.52
T243 17337-17522 Sentence denotes Average connectivity (AC), Connection centrality (CoC), Closeness centrality (ClC): the larger the quotient is, the more stable the network and, the less the influence made by the drug.
T244 17523-17698 Sentence denotes Disturbance total score (DTS), Average length of shortest path (APL), : the larger the quotient is, the less stable the network and, the larger the influence made by the drug.
T245 17699-17730 Sentence denotes Negative control formula: BXTM.
T246 17731-17762 Sentence denotes Positive control formula: YDBF.
T247 17763-18178 Sentence denotes M3 (Fig. 8A), a specific compound in formulae MXSG, showed eight interactions with E protein [ion channel] including Pi-sigma, Pi-alkyl and Alkyl, which were connected with TYR 57, ALA 32, ILE 46 and PRO 54, etc.; additionally, M3 (Fig. 8B) showed five interactions with nsp13 [Helicase NCB site] including Unfavorable Donor-Donor, Pi-alkyl and Alkyl, which were connected with ASN 559, ARG 409, LEU 42 and PRO 406.
T248 18179-18627 Sentence denotes S1 (Fig. 8C), a specific compound in formulae SGMH, showed seven interactions with nsp13 [Helicase ADP site] including H-bond interactions, van der waals, Amide-Pi stacked and Pi-alkyl, which were connected with ALA 313, ASP 374, GLN 537 and SER 289, etc.; additionally, S1 (Fig. 8D) showed five interactions with PLpro including Pi-anion, Pi-Pi stacked, Pi-Pi T-shaped and Pi-alkyl, which were connected with TYR 264, ASP 164, TYR 268 and PRO 248.
T249 18628-18852 Sentence denotes X2 (Fig. 8E), a specific compound in formulae XCH, showed seven interactions with Mpro including H-bond interactions, Pi-Donor hydrogen bond and Pi-alkyl, which were connected with MET 165, GLU 166, LEU 141 and CYS 145, etc.
T250 18853-19098 Sentence denotes O2 (Fig. 8F), a specific compound in formulae Others, showed seven interactions with Mpro including H-bond interactions, Carbon hydrogen bond, Pi-anion, Pi-sulfur and Pi-alkyl, which were connected with MET 131, GLY 71, LEU 100 and CYS 115, etc.
T251 19099-19552 Sentence denotes MS1 (Fig. 9 A), a compound in formulae MXSG and SGMH, showed eleven interactions with N protein NCB site including H-bond interactions, Pi-Donor hydrogen bond, Pi-sigma, Pi-Pi stacked and Pi-alkyl, which were connected with SER 51, THR 109, ALA 50 and PRO 42, etc.; additionally, MS1 (Fig. 9B) showed five interactions with nsp14 [ExoN] including H-bond interactions and Pi-Pi stacked, which were connected with GLU 92, PHE 190, ASP 273 and VAL 91, etc.
T252 19553-19782 Sentence denotes MX16 (Fig. 9C), a compound in formulae MXSG and XCH, showed seven interactions with nsp15 [endoribonuclease] including H-bond interactions, Alkyl and Pi-alkyl, which were connected with PRO 343, VAL 275, LYS 344 and SER 293, etc.
T253 19783-20152 Sentence denotes SX1 (Fig. 9D), a compound in formulae SGMH and XCH, showed two interactions with nsp14 [N7-MTase] including Pi-Pi stacked and Pi-alkyl, which were connected with PHE 426; additionally, SX1 (Fig. 9E) showed five interactions with nsp15 [endoribonuclease] including H-bond interactions, Alkyl and Pi-alkyl, which were connected with LYS 344, LYS 289, VAL 291 and PRO 343.
T254 20153-20673 Sentence denotes WO1 (Fig. 9F), a compound in formulae WLS and Others, showed seven interactions with nsp16 [2′-O-MTase] including H-bond interactions, Carbon hydrogen bond, Pi-Pi T-shaped, Pi-alkyl and Pi-anion, which were connected with PHE 149, CYS 115, ASP 99 and SER 74, etc.; additionally, WO1 (Fig. 9G) showed seven interactions with nsp12 [RdRp without RNA] including H-bond interactions, Carbon hydrogen bond, Unfavorable Donor-Donor, Pi-cation and Pi-anion, which were connected with THR 556, ARG 553, ASP 623 and SER 682, etc.
T255 20674-20932 Sentence denotes XO1 (Fig. 9H), a compound in formulae XCH and Others, showed ten interactions with nsp12 [RdRp with RNA] including H-bond interactions, Pi-Donor hydrogen bond, Pi-Pi T-shaped and Pi-alkyl, which were connected with CYS 813, GLY 590, LYS 593 and ASP 865, etc.
T256 20933-21062 Sentence denotes Fig. 9 Schematic (3D and 2D) representation that molecular model of common compounds of the five formulae with COVID-19 proteins.
T257 21063-21324 Sentence denotes A: MS1 and N protein NCB site, B: MS1 and nsp14 [ExoN], C: MX16 and nsp15 [endoribonuclease], D: SX1 and nsp14 [N7-MTase], E: SX1 and nsp15 [endoribonuclease], F: WO1 and nsp16 [2′-O-MTase], G: WO1 and nsp12 [RdRp without RNA], H: XO1 and nsp12 [RdRp with RNA].
T258 21325-21419 Sentence denotes MS: MXSG and SGMH, MX: MXSG and XCH, SX: SGMH and XCH, WO: WLS and Others, XO: XCH and Others.
T259 21421-21490 Sentence denotes 3.7 ACE2 and CD147 expression across tissues and co-expression genes
T260 21491-21662 Sentence denotes Since 2019-nCov may enter other tissues and organs through ACE2 and CD147 binding, we firstly explored the expression and distribution of ACE2 and CD147 across 53 tissues.
T261 21663-21846 Sentence denotes Fig. 10 A showed that the 5 top expression tissues of ACE2 were terminal ileum, testis, visceral (omentum), left ventricle and kidney cortex, which are 3 fold change higher than lung.
T262 21847-21990 Sentence denotes And the 5 top expression tissues of CD147 were testis, visceral (omentum), left ventricle, aorta, atrial appendage and transformed fibroblasts.
T263 21991-22282 Sentence denotes Then, to further understand whether QFPD only targets pneumonia or 2019-nCov, we obtained 200 co-expression genes of ACE2, 200 co-expression genes of CD147, 470 pneumonia-associated proteins, 119 HCoV-associated host proteins, and 476 co-expression genes of ACE2 in colonic epithelial cells.
T264 22283-22513 Sentence denotes Fig. 10B displayed that QFPD had some common targets with these five sets, while specific 254 targets for QFPD, indicating other mechanisms of QFPD on COVID-19 in addition to 2019-nCov, pneumonia, ACE2 and CD147 related functions.
T265 22514-22587 Sentence denotes Fig. 10 ACE2 and CD147 expression across tissues and co-expression genes.
T266 22588-22590 Sentence denotes A:
T267 22591-22649 Sentence denotes Radar plot of ACE2 and CD147 expression across 53 tissues.
T268 22650-22707 Sentence denotes The expression values were converted to base-2 logarithm.
T269 22708-22766 Sentence denotes Red triangle and square mean the top 5 expression tissues.
T270 22767-22769 Sentence denotes B:
T271 22770-22995 Sentence denotes UpSet plot of proteins among QFPD, HCoV (Host_protein), pneumonia, ACE2 co-expression genes (ACE2_database), CD147 co-expression genes (CD147_database), and ACE2 co-expression genes in colonic epithelial cells (ACE2_colonic).
T272 22996-23094 Sentence denotes The horizontal bar graph at the bottom left shows the total number of proteins for each group set.
T273 23095-23184 Sentence denotes Circles and vertical lines in the x-axis mark the corresponding data sets being compared.
T274 23185-23404 Sentence denotes The vertical bar graph at the top quantitates the number of proteins in the comparisons. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
T275 23406-23505 Sentence denotes 3.8 Validation of drug positioning for QFPD against COVID-19 via the robustness of disease network
T276 23506-23640 Sentence denotes Firstly, the robustness of whole networks against formula attack was assessed to evaluate QFPD attack on the COVID-19 disease network.
T277 23641-23919 Sentence denotes Interestingly, Table 4 and Fig. 11 showed that MSXG, SGMH, XCH, WLS and Others attack on the COVID-19 network were characterized by greater disturbance score than negative control (BXTM), and increasing dependence on hub nodes, indicating greater fragility under formula attack.
T278 23920-24031 Sentence denotes In addition, SGMH, MSXG, and Others exerted higher disturbance score than the positive control (YDBF) Table 5 .
T279 24032-24123 Sentence denotes Fig. 11 Evaluation of the effect of QFPD on the robustness disturbance of COVID-19 network.
T280 24124-24229 Sentence denotes Blue normal distribution: drug attack on random networks as a null distribution for the permutation test.
T281 24230-24310 Sentence denotes Red vertical line: the disturbance rate of the drug to the real disease network.
T282 24311-24388 Sentence denotes Fist row: MXSG, second row: SGMH, third row: XCH, fourth row: WLS, fifth row:
T283 24389-24396 Sentence denotes Others.
T284 24397-24675 Sentence denotes Fist column: average connectivity, second row: average length of shortest path, third row: connection centrality, fourth row: closeness centrality. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
T285 24676-24756 Sentence denotes Table 5 Docking score between common ingredients of QFPD and 2019-nCov proteins.
T286 24757-24804 Sentence denotes Molecule MS1 MX16 MX17 MX8 MXO1 SO1 SX1 WO1 XO1
T287 24805-24861 Sentence denotes Main Protease −7.6 −7 −7.8 −7.8 −7.8 −7.2 −7.1 −7.4 −7.4
T288 24862-24925 Sentence denotes Papain-like protease −8 −8.2 −8.1 −8.1 −8.2 −8.2 −9.2 −8.7 −8.3
T289 24926-24980 Sentence denotes RdRp with RNA −8.6 −8 −7.9 −7.9 −8 −8.4 −8.2 −8.8 −9.5
T290 24981-25040 Sentence denotes RdRp without RNA −7.1 −6.8 −6.8 −6.8 −7 −7.1 −6.9 −7.5 −7.1
T291 25041-25103 Sentence denotes Helicase ADP site −6.2 −6.5 −6.3 −6.1 −6.2 −6.4 −6.8 −6.2 −6.8
T292 25104-25166 Sentence denotes Helicase NCB site −7.4 −7.1 −7.2 −7.2 −7.5 −7.5 −7.4 −7.6 −7.5
T293 25167-25221 Sentence denotes Nsp14(ExoN) −7.2 −6.6 −6.6 −6.7 −6.9 −7 −6.9 −7.1 −7.1
T294 25222-25282 Sentence denotes Nsp14(N7-MTase) −8.6 −8.3 −8.4 −8.3 −8.6 −8.3 −9.4 −8.7 −8.7
T295 25283-25351 Sentence denotes Nsp15(endoribonuclease) −6.2 −6.8 −6.4 −6.4 −6.3 −6.5 −6.8 −6.4 −6.6
T296 25352-25414 Sentence denotes Nsp16(2′-O-MTase) −8.1 −7.4 −7.6 −7.8 −7.8 −8.3 −7.7 −8.4 −8.2
T297 25415-25474 Sentence denotes N protein NCB site −8.1 −7.9 −8 −8 −7.6 −7.8 −7.5 −7.7 −7.9
T298 25475-25542 Sentence denotes E protein(ion channel) −6.4 −6.9 −7.2 −7.2 −6.9 −6.9 −7.9 −6.8 −6.8
T299 25543-25571 Sentence denotes M: MXSG, S: SGMH, X: XCH, O:
T300 25572-25579 Sentence denotes Others.
T301 25580-25714 Sentence denotes Next, to illustrate the mechanism of QFPD against COVID-19, a formula-attacked target-KEGG pathway network was constructed (Fig. 12 ).
T302 25715-26068 Sentence denotes This network showed that MSXG, SGMH, XCH, WLS and Others interacted with 8 drug-attacked nodes (Cdc20, Ido1, Ifng, Il10, Il6, Ptger4, Spi1, Tnf), and 24 drug-attacked nodes in the COVID-19 network were related to Graft-versus-host disease, cytokine-cytokine receptor interaction, asthma, influenza A, inflammatory bowel disease, JAK-STAT signaling, etc.
T303 26069-26127 Sentence denotes Fig. 12 Disturbance analysis of QFPD for COVID-19 network.
T304 26128-26130 Sentence denotes A:
T305 26131-26183 Sentence denotes Venn diagram of the five formulae’ attacked targets.
T306 26184-26186 Sentence denotes B:
T307 26187-26315 Sentence denotes Formula-attacked target-KEGG pathway network; green square: formula, yellow diamond: attacked target, red circle: KEGG pathways.
T308 26316-26509 Sentence denotes The bigger the size of the nodes is, the higher the degree is. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)