LitCovid-sentences  

PMC:7755033 / 30391-104009 JSONTXT 3 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T262 0-2 Sentence denotes 3.
T263 4-11 Sentence denotes Results
T264 13-17 Sentence denotes 3.1.
T265 19-185 Sentence denotes Virtual screening of prospective antiviral candidates from WS phytoconstituents on the basis of physicochemical parameters and Lipinski’s rule of five (PASS analysis)
T266 186-416 Sentence denotes In the drug discovery context, it is generally believed that an orally active drug candidate cannot have more than one violation of Lipinski’s criteria otherwise it might compromise its bioavailability (Balakrishnan et al., 2014).
T267 417-551 Sentence denotes Based on Lipinski's rule of five, WS phytoconstituents were previously screened and selected for their drug like properties (Table 2).
T268 552-653 Sentence denotes As is evident from Table 2, none of the selected WS phytoconstituents exhibited Lipinski’s violation.
T269 654-774 Sentence denotes Interestingly, standard reference drugs cinacalcet and poziotinib displayed 1 violation each of Lipinski’s rule of five.
T270 775-783 Sentence denotes Table 2.
T271 785-958 Sentence denotes PASS analysis of WS phytoconstituents versus FDA-approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib).
T272 959-985 Sentence denotes Physicochemical properties
T273 986-988 Sentence denotes S.
T274 989-992 Sentence denotes No.
T275 994-1034 Sentence denotes Ligands Lipinski’s rule of 5 parameters
T276 1035-1256 Sentence denotes % Absorption(>50%)a Topological polar surface area (Å)2(TPSA)b(<160 Å) MW (<500) clog Pc(<5) Hydrogen bond donors(NOHNH)(≤5) Hydrogen bond acceptors(NON)≤10) Number of rotatable bonds(≤10) Lipinski’s violation (LV)
T277 1257-1259 Sentence denotes 1.
T278 1261-1313 Sentence denotes Withaferin A 75.76 96.36 470.61 2.49 2 6 3 0
T279 1314-1316 Sentence denotes 2.
T280 1318-1371 Sentence denotes Withanolide A 75.76 96.36 470.61 2.56 2 6 2 0
T281 1372-1374 Sentence denotes 3.
T282 1376-1429 Sentence denotes Withanolide B 82.74 76.13 454.61 3.42 1 5 2 0
T283 1430-1432 Sentence denotes 4.
T284 1434-1487 Sentence denotes Withanolide D 75.76 96.36 470.61 2.56 2 6 2 0
T285 1488-1490 Sentence denotes 5.
T286 1492-1546 Sentence denotes Withanolide E 68.78 116.59 486.61 1.77 3 7 2 0
T287 1547-1549 Sentence denotes 6.
T288 1551-1600 Sentence denotes Withanone 75.76 96.36 470.61 2.60 2 6 2 0
T289 1601-1603 Sentence denotes 7.
T290 1605-1662 Sentence denotes Viscosalactone B 68.78 116.59 488.62 1.92 3 7 3 0
T291 1663-1665 Sentence denotes 8.
T292 1667-1716 Sentence denotes Anaferine 94.81 41.12 224.35 1.47 2 3 4 0
T293 1717-1719 Sentence denotes 9.
T294 1721-1774 Sentence denotes Withasomnine 102.85 17.83 184.24 2.65 0 2 1 0
T295 1775-1778 Sentence denotes 10.
T296 1780-1826 Sentence denotes Losartan 77.09 92.5 422.9 3.95 2 5 8 0
T297 1827-1830 Sentence denotes 11.
T298 1832-1883 Sentence denotes Procainamide 88.85 58.4 235.33 0.93 2 3 6 0
T299 1884-1887 Sentence denotes 12.
T300 1889-1936 Sentence denotes Cinacalcet 104.86 12 357.4 5.65 1 4 6 1
T301 1937-1940 Sentence denotes 13.
T302 1942-1984 Sentence denotes Arbidol 81.4 80 477.4 4.17 1 5 8 0
T303 1985-1988 Sentence denotes 14.
T304 1990-2048 Sentence denotes Hydroxychloroquine 92.31 48.38 335.88 3.08 2 4 9 0
T305 2049-2052 Sentence denotes 15.
T306 2054-2100 Sentence denotes Oberadilol 67.95 119 484 2.80 4 7 10 0
T307 2101-2104 Sentence denotes 16.
T308 2106-2154 Sentence denotes Poziotinib 82.57 76.6 491.3 5.29 1 7 6 1
T309 2155-2265 Sentence denotes Rule: aPercentage absorption was calculated as: % absorption = 109 – [0.345 × topological polar surface area].
T310 2266-2358 Sentence denotes bTopological polar surface area (defined as a sum of surfaces of polar atoms in a molecule).
T311 2359-2432 Sentence denotes cLogarithm of compound partition coefficient between n-octanol and water.
T312 2433-2505 Sentence denotes WS phytoconstituents were further analyzed using additional filters viz.
T313 2506-2568 Sentence denotes Ghose, Veber, Egan, Muegge and Leadlikeness filters (Table 3).
T314 2569-2700 Sentence denotes The selected phytoconstituents showed no violations of Veber, Egan and Muegge filters thereby indicating their drug-like character.
T315 2701-2852 Sentence denotes The drug cinacalcet showed 1 and 2 violations of Egan and Muegge filters, respectively, whereas drug poziotinib exhibited 1 violation of Muegge filter.
T316 2853-2861 Sentence denotes Table 3.
T317 2863-3042 Sentence denotes Drug-like character of WS phytoconstituents versus FDA-approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib).
T318 3043-3045 Sentence denotes S.
T319 3046-3049 Sentence denotes No.
T320 3051-3131 Sentence denotes Ligands GNo. of vio.a VNo. of vio.b ENo. of vio.c MNo. ofvio.d Leadlikeness
T321 3132-3134 Sentence denotes 1.
T322 3136-3163 Sentence denotes Withaferin A 1 0 0 0 2
T323 3164-3166 Sentence denotes 2.
T324 3168-3196 Sentence denotes Withanolide A 1 0 0 0 1
T325 3197-3199 Sentence denotes 3.
T326 3201-3229 Sentence denotes Withanolide B 1 0 0 0 2
T327 3230-3232 Sentence denotes 4.
T328 3234-3262 Sentence denotes Withanolide D 1 0 0 0 1
T329 3263-3265 Sentence denotes 5.
T330 3267-3295 Sentence denotes Withanolide E 2 0 0 0 1
T331 3296-3298 Sentence denotes 6.
T332 3300-3324 Sentence denotes Withanone 1 0 0 0 1
T333 3325-3327 Sentence denotes 7.
T334 3329-3360 Sentence denotes Viscosalactone B 1 0 0 0 1
T335 3361-3363 Sentence denotes 8.
T336 3365-3389 Sentence denotes Anaferine 0 0 0 0 1
T337 3390-3392 Sentence denotes 9.
T338 3394-3421 Sentence denotes Withasomnine 0 0 0 0 1
T339 3422-3425 Sentence denotes 10.
T340 3427-3450 Sentence denotes Losartan 0 0 0 0 3
T341 3451-3454 Sentence denotes 11.
T342 3456-3483 Sentence denotes Procainamide 0 0 0 0 1
T343 3484-3487 Sentence denotes 12.
T344 3489-3514 Sentence denotes Cinacalcet 1 0 1 2 2
T345 3515-3518 Sentence denotes 13.
T346 3520-3542 Sentence denotes Arbidol 0 0 0 0 3
T347 3543-3546 Sentence denotes 14.
T348 3548-3581 Sentence denotes Hydroxychloroquine 0 0 0 0 2
T349 3582-3585 Sentence denotes 15.
T350 3587-3612 Sentence denotes Oberadilol 2 0 0 0 2
T351 3613-3616 Sentence denotes 16.
T352 3618-3643 Sentence denotes Poziotinib 2 0 0 1 2
T353 3644-3664 Sentence denotes Rule: aGhose filter.
T354 3665-3679 Sentence denotes bVeber filter.
T355 3680-3706 Sentence denotes cEgan (Pharmacial) filter.
T356 3707-3730 Sentence denotes dMuegge (Bayer) filter.
T357 3732-3788 Sentence denotes 3.2. admetSAR analysis of selected WS phytoconstituents
T358 3789-3865 Sentence denotes Good ADME and toxicity properties are as critical as therapeutic properties.
T359 3866-4086 Sentence denotes Human intestinal absorption (HIA), Caco-2 cell permeability, Blood–brain barrier (BBB) penetration, and Ames test were calculated for the chosen phytoconstituents and reference drugs using admetSAR version 1.0 (Table 4).
T360 4087-4285 Sentence denotes Table 4. admetSAR prediction of selected WS phytoconstituents versus FDA-approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib).
T361 4286-4504 Sentence denotes Ligands Human intestinal absorption (HIA) Caco-2 permeability P-glycoprotein inhibitor Blood–brain barrier penetration (BBB) Ames mutagenesis Subcellular localization Biodegradation Acute oral toxicity (kg/mol)
T362 4505-4587 Sentence denotes ± p value ± p value ± p value ± p value ± p value ± p value ± p value
T363 4588-4695 Sentence denotes Withaferin A + 0.9729 – 0.6673 + 0.6132 + 0.9537 – 0.6900 Mitochondria 0.7714 – 0.8750 3.276
T364 4696-4804 Sentence denotes Withanolide A + 0.9829 – 0.6006 + 0.6554 + 0.8333 – 0.8700 Mitochondria 0.6830 – 0.8000 5.165
T365 4805-4913 Sentence denotes Withanolide B + 0.9829 – 0.5605 + 0.7494 + 0.9128 – 0.8000 Mitochondria 0.6784 – 0.8750 4.099
T366 4914-5021 Sentence denotes Withanolide D + 0.9750 – 0.6274 – 0.4303 + 0.8345 – 0.7800 Mitochondria 0.7352 – 0.8250 3.66
T367 5022-5130 Sentence denotes Withanolide E + 0.9640 – 0.6455 – 0.4399 – 0.5510 – 0.7100 Mitochondria 0.6273 – 0.9250 5.292
T368 5131-5235 Sentence denotes Withanone + 0.9829 – 0.6472 + 0.6845 + 0.8333 – 0.8300 Mitochondria 0.6830 – 0.8500 4.775
T369 5236-5347 Sentence denotes Viscosalactone B + 0.9480 – 0.7386 – 0.4906 + 0.9214 – 0.7500 Mitochondria 0.7598 – 0.8250 3.059
T370 5348-5452 Sentence denotes Anaferine + 0.9064 + 0.5418 – 0.9112 + 0.9929 – 0.7300 Mitochondria 0.7672 – 0.7000 2.517
T371 5453-5559 Sentence denotes Withasomnine + 0.9932 + 0.9586 – 0.9813 + 0.9966 – 0.9100 Mitochondria 0.5372 – 0.8750 2.41
T372 5560-5663 Sentence denotes Losartan + 0.9883 – 0.9373 + 0.8124 – 0.9930 – 0.5200 Mitochondria 0.7540 – 0.9250 3.322
T373 5664-5767 Sentence denotes Procainamide + 0.9795 + 0.9185 – 0.9721 + 0.9707 – 0.5900 Lysosomes 0.8295 – 0.6000 2.59
T374 5768-5870 Sentence denotes Cinacalcet + 0.9911 + 0.7035 + 0.5803 + 0.9974 – 0.5000 Lysosomes 0.9070 – 1.0000 3.492
T375 5871-5970 Sentence denotes Arbidol + 0.9684 + 0.6814 + 0.6810 + 0.9739 + 0.5300 Lysosomes 0.5338 – 0.9000 2.753
T376 5971-6081 Sentence denotes Hydroxychloroquine + 0.9934 + 0.5313 – 0.7900 + 0.9878 + 0.6400 Lysosomes 0.8067 – 0.8500 2.665
T377 6082-6187 Sentence denotes Oberadilol + 0.9820 – 0.7895 + 0.7739 + 0.9693 – 0.6300 Mitochondria 0.8157 – 0.7250 3.747
T378 6188-6293 Sentence denotes Poziotinib + 0.9852 – 0.6765 + 0.8852 + 0.9900 – 0.5600 Mitochondria 0.5163 – 0.9000 3.121
T379 6295-6301 Sentence denotes 3.2.1.
T380 6303-6336 Sentence denotes Human intestinal absorption (HIA)
T381 6337-6404 Sentence denotes An orally administered drug is absorbed primarily in the intestine.
T382 6405-6559 Sentence denotes All WS phytoconstituents and standard reference drugs exhibited positive results, thereby indicating their absorption and assimilation in human intestine.
T383 6561-6567 Sentence denotes 3.2.2.
T384 6569-6588 Sentence denotes Caco-2 permeability
T385 6589-6727 Sentence denotes Caco-2 is a human colon epithelial cancer cell line and is used as a model for human intestinal assimilation of drugs and other compounds.
T386 6728-6912 Sentence denotes In the present study, whereas anaferine and withasomnine exhibited positive results indicating Caco-2 permeability, the remaining seven WS phytoconstituents displayed negative results.
T387 6913-7072 Sentence denotes In case of standard reference drugs, procainamide, cinacalcet, arbidol and hydroxychloroquine displayed good permeability characteristics for Caco-2 (Table 4).
T388 7074-7080 Sentence denotes 3.2.3.
T389 7082-7119 Sentence denotes Blood–brain barrier (BBB) penetration
T390 7120-7201 Sentence denotes An important consideration for drug candidates is their ability to cross the BBB.
T391 7202-7309 Sentence denotes All of the chosen WS phytoconstituents displayed positive results for BBB penetration except withanolide E.
T392 7310-7412 Sentence denotes In case of standard reference drugs, only losartan displayed inability to penetrate the BBB (Table 4).
T393 7414-7420 Sentence denotes 3.2.4.
T394 7422-7431 Sentence denotes Ames test
T395 7432-7679 Sentence denotes In the present study, none of the chosen WS phytoconstituents were predicted to have any mutagenic effect in contrast to standard reference drugs arbidol and hydroxychloroquine which tested positive for their ability to induce mutations (Table 4).
T396 7681-7685 Sentence denotes 3.3.
T397 7687-7767 Sentence denotes Docking studies of WS phytoconstituents with respect to selected target proteins
T398 7768-7906 Sentence denotes Docking studies of the selected WS phytoconstituents were carried out with human ACE2 receptor, SARS-CoV and SARS-CoV-2 specific proteins.
T399 7907-8144 Sentence denotes The catalytically active sites of SARS-CoV-2 specific proteins were targeted in order to obtain the binding energy involved in the complex formation and to discover the molecular mechanisms responsible for specific inhibition of targets.
T400 8145-8392 Sentence denotes Tables 5–11 summarize the predicted binding energies and dissociation constants (Kd) of WS phytoconstituents with respect to specific human ACE2 receptor, SAR-CoV and SARS-CoV-2 spike glycoproteins as well as the two main SARS-CoV-2 proteases viz.
T401 8393-8412 Sentence denotes 3CL-pro and PL-pro.
T402 8413-8628 Sentence denotes The binding sites of the WS phytoconstituents on the selected viral target proteins as well as the interacting amino acids were predicted to be almost the same by the three molecular docking softwares (Tables 5–11).
T403 8629-8744 Sentence denotes The common interacting amino acids between the three softwares have been written in italicized form in Tables 5–11.
T404 8745-8876 Sentence denotes As is evident from Tables 5–11, most of the WS phytoconstituents exhibited potent binding kinetics to the above-mentioned proteins.
T405 8877-9190 Sentence denotes Docking analyses using AutoDock 4.0/ADT version 4.2.6 program revealed that the binding affinities of the WS phytoconstituents for the human ACE2 receptor decreased in the order withanolide B > withanolide A > withanolide E > viscosalactone B > withaferin A > anaferine > withanolide D > withanone > withasomnine.
T406 9191-9297 Sentence denotes Withanolide B exhibited a 1000× stronger binding to human ACE2 receptor (Table 5; BE: −10.21 kcal/mol, Kd:
T407 9298-9390 Sentence denotes 32.78 nM) as compared to standard reference drugs, arbidol (Table 5; BE: −6.69 kcal/mol, Kd:
T408 9391-9447 Sentence denotes 12.47 µM) and losartan (Table 5; BE: –6.72 kcal/mol, Kd:
T409 9448-9458 Sentence denotes 11.86 µM).
T410 9459-9573 Sentence denotes Withanolide B also exhibited potent binding to papain like protease of SARS-CoV-2 (Table 8; BE −10.3 kcal/mol, Kd:
T411 9574-9644 Sentence denotes 28.32 nM) as compared to procainamide (Table 8; BE −5.03 kcal/mol, Kd:
T412 9645-9703 Sentence denotes 206.96 µM) and cinacalcet (Table 8; BE −6.44 kcal/mol, Kd:
T413 9704-9714 Sentence denotes 19.17 µM).
T414 9715-9723 Sentence denotes Table 5.
T415 9725-9799 Sentence denotes Binding energies of WS phytoconstituents with human ACE2 receptor (PDB ID:
T416 9800-9888 Sentence denotes 1O8A) in comparison to the FDA approved standard reference drugs (Arbidol and Losartan).
T417 9889-9937 Sentence denotes   AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T418 9938-9940 Sentence denotes S.
T419 9941-9944 Sentence denotes No.
T420 9946-10099 Sentence denotes Ligands BE (kcal/mol) K d Interacting amino acids BE(kcal/mol) K d Interacting amino acids TE(kcal/mol) VDW HB EI Interacting amino acids  
T421 10100-10102 Sentence denotes 1.
T422 10104-10584 Sentence denotes Withaferin A –8.44 647.61 nM Glu123, Met223, Trp220, Pro519, Arg522, Ser517, Val518, Glu411, His410, Ser355, Ala356, His387, Phe391, Glu403 –10.4 23.67 nM His353, Val518, His513, Tyr523, Glu411, Arg522, Phe512, Ala356, Ser355, Ser516, Glu143, Asn70, Asn66, Tyr69, Leu140, Leu139, Leu81, Asn85, Tyr62, Asn136, Arg124 –111.33 –90.07 –21.26 0 Ser284, Tyr287, Val291, Asp288, Asn285, Glu376, Leu375, Asn374, Thr302, Thr301, Asp300, Met299, Ser298, Pro297, Pro294, Ala296  
T423 10585-10587 Sentence denotes 2.
T424 10589-11001 Sentence denotes Withanolide A –10.13 37.44 nM Asp453, Thr282, Gln281, Phe457, Glu376, Val379, Val380, Asp415, His383, Glu384, Ala354, His353, His387, Glu411, His513, Phe512, Tyr523 –10.6 15.57 nM His410, Ala353, His387, Trp357, Phe391, Asn66, Asn70, Ser516, Glu143, Phe512, Val518, His353, Ser355, His513, Tyr523, Glu411, Arg522 –98.26 –78.36 –19.90 0 Leu375, Lys449, Tyr287, Ser298, Met299, Asp300, Thr301, Thr302  
T425 11002-11004 Sentence denotes 3.
T426 11006-11486 Sentence denotes Withanolide B –10.21 32.78 nM Phe391, His387, Ala356, His383, Ser355, Ala354, His353, Glu403, Gly404, His410, Glu411, Pro407, Tyr523, Arg522, Phe512, His513, Met223 –10.7 10.60 nM Asn85, Tyr62, Arg124, Asn66, Phe512, His353, Val518, His513, Tyr523, Arg522, Glu411, Leu81, Leu140, Leu139, Tyr69, Glu143, Asn70, Ser516, Ser355, Ala356, His387 –97.61 –86.31 –11.29 0 Thr226, Glu225, Pro227, Tyr224, Leu229, Ser222, Arg221, Asp218, Tyr213, Asn211, Asp121, Gln120, Lys117  
T427 11487-11489 Sentence denotes 4.
T428 11491-11944 Sentence denotes Withanolide D –8.23 934.88 nM Phe391, Ala356, Ser355, His387, Glu384, Ala354, His353, Glu411, Tyr523, Val518, His383, Val380 –11.3 600 pM Glu411, Tyr523, Arg522, His410, Phe391, Ala356, His387, Asn66, Asn70, Tyr69, Trp357, Glu143, Val351, Ser516, Phe512, His353,Val518, Ser355 –101.56 –82.00 –19.56 0 Arg124, Leu140, Leu81, Glu143, Asn66, Asn70, Tyr69, His353, Ala354, Ser355, Ala356, Glu384, His387, Glu411, Tyr523, Val518, His513, Phe512  
T429 11945-11947 Sentence denotes 5.
T430 11949-12396 Sentence denotes Withanolide E –9.75 71.2 nM Phe391, His410, His387, Glu411, Arg522, Tyr523, Val518, His513, Phe512, His353, Ala354, Ser355, Glu384, Ala356, Lys368, Asn70 –10.6 15.45 nM Arg124, Leu140, Leu139, Leu81, Asn70, Tyr69, Glu143, Ser516, Val351, Trp357, Phe512, His353, Ser355, Ala356, Glu384, His387, Phe391, Val518, Tyr62, Asn66 –104.39 –90.97 –13.41 0 Glu239, Arg235, Leu236, Asp232, Ser228, Thr226, Pro575, Trp574, Pro585, Asn586, Met587  
T431 12397-12399 Sentence denotes 6.
T432 12401-12810 Sentence denotes Withanone –8.12 1.12 µM Ser422, Phe527, Lys454, Tyr523, Val379, His383, Glu384, Val380, His513, Gln281, Thr282, Ser284, Phe457, Asp453 –10.2 31.56 nM Lys449, Val291, Pro297, Ser298, Asp300, Met299, Ser284, Asn285, Asn374, Glu376, Thr302, Leu375, Thr301, Tyr287, Asp288 –100.15 –79.22 –20.92 0 Asn374, Leu375, Thr302, Thr301, Asp300, Met299, Ser298, Pro297, Ala296, Pro294, Val291, Tyr287, Asn285  
T433 12811-12813 Sentence denotes 7.
T434 12815-13354 Sentence denotes Viscosalactone B –8.83 339.1 nM Ala356, His387, Ser355, Glu384, Ala354, His353, His513, Phe512, Tyr523, Thr282, Asp453, Ser284, Glu376, Val379, Val380, His383, Glu411 –11.1 760 pM Tyr62, Asn85, Asn136, Leu81, Glu143, Leu139, Leu140, Asn66,Asn70, Phe512, Ala356, Ser355, Ala354, His353, Tyr523, His383, His387, Glu411, Arg522, Val518, Arg124 –119.88 –92.25 –27.63 0 Tyr62, Leu81,Asn136, Asn66, Tyr69, Leu139, Leu140, Glu143, Ser516, Asn70, His513, His353, Ala354, Tyr523, Ser355, Ala356, Trp357, His387, Glu411, Glu384, His383  
T435 13355-13357 Sentence denotes 8.
T436 13359-13710 Sentence denotes Anaferine –8.25 890.86 nM Glu411, Tyr523, His383, His387, Glu384, Val380, Ala356, Ser355, Ala354, His353 –6.7 12.50 µM His383, His387, Ala354, Glu384, Ser355, Ala356, Val518, His513, Phe512, His353, Tyr523, Tyr520, Gln281, Phe457, Phe527 –77.85 –74.35 –3.5 0 Phe570, Met223, Asn406, Glu403, Gly404, Pro407, His410, Phe391, Glu411, His387  
T437 13711-13713 Sentence denotes 9.
T438 13715-14018 Sentence denotes Withasomnine –4.99 218.08 µM Tyr523, His513, Val380, His383, Glu384, His387, Ala356, Ser355, Ala354, His353 –6.7 12.59 µM Phe291, Tyr394, His410, Arg522, Gly404, Pro407, Glu403, Met223, Phe570, Asn406 –74.24 –64.10 –10.14 0 Leu122, Thr92, Ala125, Arg124, Ala89, Ile88, Asn85, Asn136, Trp59  
T439 14019-14022 Sentence denotes 10.
T440 14024-14467 Sentence denotes Arbidol –6.69 12.47 µM Ala354, His353, Glu162, Lys511, Trp279, Gln281, Thr282, Phe457, Asp453, Tyr523, Lys454, Phe527, Asp415, His383, Val380, Glu384 –8.3 880.23 nM Phe570, Met223, Asn406, Gly404, Glu403, Arg402, Tyr394, Tyr360, Phe391, Asp358, Trp357, Ala356,His387, His410, Glu411, Arg522, Pro407 –86.22 –73.55 –12.67 0 Phe391, His410, Glu411, His387, Trp357, Ala356, Ser355, Ala354, His353, Asn66, Ala63, Tyr62, Val518, Tyr523  
T441 14468-14471 Sentence denotes 11.
T442 14473-14887 Sentence denotes Losartan –6.72 11.86 µM Asn406, Met223, Arg522, Pro407, Gly404, Glu403, His410, Glu411, Tyr523, Phe391, His387, Ala356, Val518 –9.4 129.59 nM Met223, Pro519, Arg522, His410, His387, Tyr523, Glu411, Ser355, Val518, Ala356, Asp358, Tyr360, Phe391, Gly404, Glu403, Asn406, Pro407 –101.28 –85.24 –16.04 0 Asp121, Leu122, Thr92, Trp220, Glu123, Arg124, Ala89, Ile88, Pro519, Tyr62, Ser517, Tyr135, Ile204  
T443 14888-14896 Sentence denotes Table 6.
T444 14898-14980 Sentence denotes Binding energies of WS phytoconstituents with SARS-CoV spike glycoprotein (PDB ID:
T445 14981-15079 Sentence denotes 5WRG) in comparison to the FDA approved standard reference drugs (Arbidol and Hydroxychloroquine).
T446 15080-15128 Sentence denotes   AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T447 15129-15131 Sentence denotes S.
T448 15132-15135 Sentence denotes No.
T449 15137-15290 Sentence denotes Ligands BE (kcal/mol) K d Interacting amino acids BE(kcal/mol) K d Interacting amino acids TE(kcal/mol) VDW HB EI Interacting amino acids  
T450 15291-15293 Sentence denotes 1.
T451 15295-15693 Sentence denotes Withaferin A –8.39 702.21 nM Ile979, Leu983, Thr980, Gly981, Gln984, Tyr738, Leu983, Gln984, Thr980 –10.3 28.30 nM Lys715, Ala753, Ala754, Asp757, Arg761, Leu846, Arg758, Pro651, Ile652, Leu843, Leu597, Gln599, Ala633, Val581, Tyr300, Thr302 –104.25 –83.69 –20.56 0 Arg453, Glu452, Asp454, Ser456, Arg449, Arg441, Val458, Pro459, Arg444, His445, Phe460, Pro466, Gly464, Ser461, Lys465  
T452 15694-15696 Sentence denotes 2.
T453 15698-16054 Sentence denotes Withanolide A –9.78 67.23 nM Gln984,Leu983, Thr980, Gly981, Arg977, Phe952, Tyr738 –10.5 19.50 nM Ile299, Ala754, Ser750, Thr302, Ala753, Val581, Leu843, Gln599, Ile652, Arg758, Lys715, Gly653, Asp757, Tyr300, Arg761, Pro651, Leu846 –97.67 –85.32 –12.35 0 Ile652, Pro651, Thr302, Tyr300, Ile299, Gln301, Ser750, Ala754, Arg747, Gly751, Lys715  
T454 16055-16057 Sentence denotes 3.
T455 16059-16399 Sentence denotes Withanolide B –9.4 129.59 nM Gln984, Thr980, Leu983, Gly981, Arg977, Phe952, Tyr738, Asp976 –10.4 23.67 nM Ser950, Asn951, Gly981, Arg977,Thr980, Asp976, Asp976, Phe952,Gln984, Leu983, Gln947, Phe741, Ser985, Tyr738 –100.62 –94.31 –6.32 0 Lys715, Asp757, Ala753, Arg761, Arg758, Ala754, Leu846, Gly653, Ile652, Pro651, Tyr300  
T456 16400-16402 Sentence denotes 4.
T457 16404-16784 Sentence denotes Withanolide D –9.1 212.78 nM Thr980, Gly981, Leu983, Tyr738, Phe952, Gln984, Asp976, Ile979 –10.7 11.45 nM Ile299, Ala754, Pro651, Arg758, Arg761, Asp757, Leu846, Leu597, Lys715, Val581, Ile652, Ala633, Gln599, Leu843, Tyr300, Ser750, Ala753, Thr302 –103.3 –84.53 –18.77 0 Ala926,Leu927, Ser924, Gly928, Thr925, Gln931, Asn935, Lys297, Asp296, Ile295, Glu294, Val290  
T458 16785-16787 Sentence denotes 5.
T459 16789-17166 Sentence denotes Withanolide E –7.13 5.93 µM Thr980, Gly981, Gln984, Arg977, Tyr738, Leu983 –9.5 99.21 nM Lys715, Ala753, Ser750, Pro844, Thr302, Leu843, Ala633,Gln599, Ile652, Leu597, Val581, Ile299, Pro651, Ile650, Tyr300, Ala754 –99.34 –93.84 –5.49 0 Leu597,Ala633, Gln599, Ile652, Val581, Pro651, Thr302, Ile650, Tyr300, Ile299, Pro844, Leu843, Lys715, Ser750, Ala753, Ala754  
T460 17167-17169 Sentence denotes 6.
T461 17171-17515 Sentence denotes Withanone –6.49 17.46 µM Thr980, Gly981, Gln984, Leu983, Phe741,Tyr738 –9.5 99.56 nM Arg747, Gly751, Ala754, Pro651, Ile652, Lys715, Gln599, Val581, Tyr200, Leu843, Ala753, Thr302, Ser750, Ile299, Gln939, Gln301 –104.09 –85.03 –19.07 0 Leu810, Ala938, Asn942, Lys946, Thr943, Gln744, Arg747, Thr743, Ser289, Gln301, Val290, Lys291  
T462 17516-17518 Sentence denotes 7.
T463 17520-17944 Sentence denotes Viscosalactone B –7.6 2.69 µM Gln987, Gln984, Leu983, Thr980, Asp976, Phe952, Gly981, Gln984, Thr988 –10.2 32.60 nM Leu994, Ile995, Glu999, Ala998, Ile752, Arg1001, Ala997, Glu755, Gln936, Asp932, Ile299, Asp296, Tyr300, Gln301, Gln939, Arg747, Ala748, Gly751, Arg996 –121.82 –89.39 –32.43 0 Arg563, Arg315, Phe551, Gln550, Asn530, Gly531, Asn505, Leu504, Leu503, Ser380, Phe379, Cys378, Arg965, Asn530, Gly551  
T464 17945-17947 Sentence denotes 8.
T465 17949-18283 Sentence denotes Anaferine –6.94 8.16 µM Gln947, Phe741, Ser985, Gln984, Gly981, Tyr738, Phe952, Leu983, Thr980, Ile979, Asp976 –7.0 6.40 µM Arg747, Thr943, Gln744, Thr988, Gln987, Phe741, Gln947, Ser985, Tyr989, Leu944, Ala940, Gln992 –84.12 –69.13 –14.99 0 Arg965, Leu374, Lys373, Tyr352, Cys378, Leu503, Phe501, Met417, Val369, Ser370  
T466 18284-18286 Sentence denotes 9.
T467 18288-18601 Sentence denotes Withasomnine –5.87 49.69 µM Gln947, Phe741, Ser985, Gln984, Gly981, Leu983, Phe952, Asn951, Tyr738, Ser950 –7.1 6.25 µM Leu963, Ser728, Cys725, Val958, Leu948, Phe558, Asp557, Phe837, Asn960, Thr535, Thr533, Asp727, Leu959 –80.03 –72.43 –7.60 0 Cys278, Phe262, Met263, Val276, Cys288, Lys287, Ser292  
T468 18602-18605 Sentence denotes 10.
T469 18607-18673 Sentence denotes Arbidol –4.91 251.65 µM Phe952, Gln947, Gly739, Phe741, Tyr738.
T470 18674-18927 Sentence denotes Gly981, Arg977, Thr980, Asp976, Thr980, Leu983, Gln984 –7.7 2.20 µM Ala754, Ser750, Asn746, Arg747, Thr302, Gln599, Gln301, Val581, Tyr300 –83.02 –78.02 –5 0 Leu859, Pro1035, Phe1034, Ser1033, Cys1014, Val1015, Gln883, Leu1016, Pro879, Gly862  
T471 18928-18931 Sentence denotes 11.
T472 18933-19264 Sentence denotes Hydroxychloroquine –5.25 142.18 µM Gln984, Leu983, Thr980, Ile979,Ser985, Gly981, Phe741, Gln947, Tyr738, Phe952 –7.0 7.0 µM Ala753, Ser750, Pro651, Lys715, Leu843, Gly653, Ile652, Val581, Tyr300, Thr302, Gln599, Leu597, Ile299, Ala754 –76.22 –68.13 –8.09 0 Lys1027, Gly1026, Val1022, Ser1012, Val1015, Gln766, Lys768  
T473 19265-19273 Sentence denotes Table 7.
T474 19275-19453 Sentence denotes Binding energies of WS phytoconstituents with SARS-CoV-2 spike glycoprotein (PDB ID:6VXX) in comparison to FDA approved standard reference drugs (Arbidol and Hydroxychloroquine).
T475 19454-19505 Sentence denotes     AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T476 19506-19508 Sentence denotes S.
T477 19509-19512 Sentence denotes No.
T478 19514-19664 Sentence denotes Ligands BE (kcal/mol) K d Interacting amino acids BE(kcal/mol) K d Interacting amino acids TE(kcal/mol) VDW HB EI Interacting amino acids
T479 19665-19667 Sentence denotes 1.
T480 19669-19978 Sentence denotes Withaferin A –6.11 33.39 µM Leu303, Tyr313, Thr302, Gln314, Thr315, Ser316, Asn317, Arg319 –8.6 447.56 nM Gln218, Phe59, Gly219, Phe220, Thr33, Asp287, Phe58, Val289, Ser297, Lys300, Asp294, Leu296, Asn606, Leu293 –84.45 –66.52 17.93 0 Thr430, Asp428, Phe515, Ser514, Glu516, Tyr396, Arg355, Phe464
T481 19979-19981 Sentence denotes 2.
T482 19983-20308 Sentence denotes Withanolide A –7.18 5.48 µM Glu309, Tyr313, Thr302, Leu303, Lys304, Gln957 –8.4 650.76 nM Leu977, Cys743, Val976, Asn978, Leu966, Ser975, Ser967, Arg44, Ser45, Val47, Asn856, Arg1000, Tyr741, Ile742 –83.67 –61.91 –21.76 0 Arg273, Pro272, Cys291, Thr274, Cys301, Gln52, Lys304, Ser50, Thr301, Thr315, Ala292, Glu298
T483 20309-20311 Sentence denotes 3.
T484 20313-20632 Sentence denotes Withanolide B –6.81 10.26 µM Gln31, Tyr313, Thr302, Leu303, Lys304, Gln957, Asn960, Lys964 –8.0 771.67 nM Arg319, Thr572, Thr573, Asp571, Arg567, Leu546, Thr547, Gly548, Phe541, Thr549, Pro589, Cys590, Phe592, Arg319 –86.89 –78.89 –7.9 0 Asn556, Ile584, Leu582, Arg577, Lys557, Lys558, Phe559, Leu560, Pro561
T485 20633-20635 Sentence denotes 4.
T486 20637-20749 Sentence denotes Withanolide D –6.9 8.68 µM Gln957, Thr961, Lys964, Gln965, Ser967, Ser968, Leu303, Lys304, Thr302 –8.7 398.
T487 20750-21006 Sentence denotes 84 nM Val976, Arg1000, Phe855, Ser975, Lys854, Val963, Asn856, Ser967, Leu966, Asn978, Leu977, Asp745, Met740, Gly744, Tyr741 –82.91 –69.68 –13.23 0 Gln954, Ala958, Thr961, Leu962, Arg1014, Glu1017, Ile1013, Gln1010, Tyr1007, Thr1006, Ser1003, Gln965
T488 21007-21009 Sentence denotes 5.
T489 21011-21279 Sentence denotes Withanolide E –6.94 8.17 µM Gln957, Lys964, Lys304, Leu303, Thr302 –8.0 771.57 nM Asn30, Phe59, Thr33, Phe58, Phe306, Val289, Ala288, Lys300, Ser297, Leu296, Leu293, Asp294 –91.24 –82.26 –8.98 0 Glu340, Gly339, Phe338, Cys336, Ala363, Asp364, Val362, Leu335
T490 21280-21282 Sentence denotes 6.
T491 21284-21570 Sentence denotes Withanone –7.15 5.75 µM Gln309, Ser305, Leu303, Lys304, Thr302, Lys964, Gln957 –8.0 771.87 nM Asn978, Val963, Lys964, Ser967, Asn856, Ser975, Val976, Leu966, Tyr741, Leu977, Arg1000, Gly744 –84.14 –69.21 –14.92 0 Pro793, Pro792, Thr791, Lys790, Pro897, Thr883, Ile896, Gln895
T492 21571-21573 Sentence denotes 7.
T493 21575-21902 Sentence denotes Viscosalactone B –6.02 38.89 µM Gln957, Ser305, Lys304, Leu303, Thr302, Thr315, Gln31, Ser316, Asn317 –8.2 935.88 nM Asn856, Gly744, Arg1000, Val976, Ser975, Ser967, Leu966, Asn978, Leu977 –98.52 –80.77 –17.75 0 Phe86, Asn87, Ile235, Asp88, Asn234, Pro272, Ile233, Leu54, Asn196, Asp53, Gln52, Ile197, Gly199, Asp198
T494 21903-21905 Sentence denotes 8.
T495 21907-22209 Sentence denotes Anaferine –3.86 1.47 mM Tyr313, Glu309, Leu303, Lys304, Gln957 –5.0 213.05 µM Ser967, Ser975, Val976, Leu977, Arg1000, Asn978, Gly744, Asp745, Met740, Phe855, Tyr741, Leu966, Asn856, Val963, Lys964 –72.56 –58.62 –13.94 0 Lys933, Ser929, Ile934, Ala930, Gln926, Thr719, Ser721, Ile720, Val722
T496 22210-22212 Sentence denotes 9.
T497 22214-22513 Sentence denotes Withasomnine –4.51 494.91 µM Ser316, Thr315, Glu298, Cys291, Thr302, Cys301, Thr274, Lys304, Ser50 –6.2 29.91 µM Ser1003, Leu962, Tyr1007, Gln957, Arg1014, Gln1010, Ala958, Thr1006, Gln965, Thr961 –73.49 –65.71 –7.78 0 Glu1111, Gln1113, Thr1105, Gln1106, Val1104, Thr912, Asn1119, Glu1092
T498 22514-22517 Sentence denotes 10.
T499 22519-22830 Sentence denotes Arbidol –3.14 4.99 mM Glu309, Tyr313, Gln314, Leu303, Thr302, Gln957, Thr961, Lys964 –5.8 56.89 µM Phe59, Thr33, Phe220, Thr286, Asp287, Ala288, Val289, Asp290, Leu293, Asp294, Leu296, Ser297, Lys300 –78.93 –72.29 –6.64 0 Thr618, Glu619, Gln644, Asn616, Val615, Asp614, Phe592, Cys590, Pro589, Thr589
T500 22831-22834 Sentence denotes 11.
T501 22836-23125 Sentence denotes Hydroxychloroquine –2.48 15.11 mM Ser50, Cys301, Glu298, Thr302, Thr315, Ser316 –6.1 35.2 µM Asp294, Leu296, Leu293, Ser297, Lys300, Val289, Asp287, Phe306, Thr33, Asn606, Thr602 –72.42 –62.92 –9.5 0 Val722, Thr724, Ile726, Ile934, Ser937, Leu938, Thr941, Ala944, Ser943, Ile726
T502 23126-23134 Sentence denotes Table 8.
T503 23136-23225 Sentence denotes Binding energies of WS phytoconstituents with papain like protease of SARS-CoV-2 (PDB ID:
T504 23226-23321 Sentence denotes 6W9C) in comparison to the FDA approved standard reference drugs (Procainamide and Cinacalcet).
T505 23322-23373 Sentence denotes     AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T506 23374-23376 Sentence denotes S.
T507 23377-23380 Sentence denotes No.
T508 23382-23532 Sentence denotes Ligands BE (kcal/mol) K d Interacting amino acids BE(kcal/mol) K d Interacting amino acids TE(kcal/mol) VDW HB EI Interacting amino acids
T509 23533-23535 Sentence denotes 1.
T510 23537-23834 Sentence denotes Withaferin A –8.74 393.84 nM Asn109, Leu162, Gly160, Gln269, Glu161, Val159, His89, Thr158 –9.8 61.88 nM His89, Val159, Gly160, Glu161,Leu162, Gln269, Asn109, Thr158 –101.80 –86.23 –15.57 0 Trp106, Ala107, Asn267, Asp108, Leu162, Gly163, Lys157, Asp164, Glu167, Tyr264, Pro248, Pro247
T511 23835-23837 Sentence denotes 2.
T512 23839-24165 Sentence denotes Withanolide A –10.19 34.04 nM Gln269, Asn109, Leu162, Glu161, Gly160, Val159, Thr158 –10.2 32.78 nM Asp286, Asn267, Asp164, Tyr264, Tyr273, Pro248, Gly163, Leu162, Lys157, Asp108, Ala107, Trp106, Gly266, Ala288, Lys105, Tyr268, Leu289 –103.61 –84.71 –18.90 0 Asn109, Val159, Thr158, Glu161, Gly160, Gln269, Leu162
T513 24166-24168 Sentence denotes 3.
T514 24170-24448 Sentence denotes Withanolide B –10.3 28.32 nM Gln269, Asn109, Leu162, Glu161, Gly160, Val159, His89, Thr158 –10.4 22.51 nM His89, Thr158, Gly160, Asn109,Gln269, Leu162, Val159 –104.57 –96.14 –8.43 0 Thr158, Leu162, Glu161, Gly160, His89, Asp108, Ser85, Ala86, Gly160, Val159, Asn109
T515 24449-24451 Sentence denotes 4.
T516 24453-24759 Sentence denotes Withanolide D –9.56 98.21 nM Gly160, Glu161, Asn109, Gln269, Cys270, Leu162, Cys160, Val159, Thr158, His89 –10.1 38.9 nM Thr158, His89, Glu161, Gly160, Asn109, Gln269, Leu162, Val159 –99.07 –91.72 –7.35 0 Pro59, Ala68, Arg65, Phe69, Thr74, Thr75, Pro77, Ile44, Lys45, Pro46, Met23, His47, Asn48
T517 24760-24762 Sentence denotes 5.
T518 24764-25032 Sentence denotes Withanolide E –9.05 231.88 nM Asn109, Gln269, Leu162, Gly160, Asp108, Glu161, His89 –10.6 15.57 nM Asp108, Thr158, Glu161, Val159, His89, Gly160, Leu162, Asn109, Gln269 –107.44 –76.48 –30.96 0 Thr158, Asn109, Gly160, Glu161, Leu162, Asp108, Val159, His89
T519 25033-25035 Sentence denotes 6.
T520 25037-25343 Sentence denotes Withanone –9.09 218.4 nM Val159, Gly160, Glu161, Asn109, Leu162, Gln269, Gln269 –10.1 38.83 nM Trp106, Glu167, Ala107, Trp93, Lys92, His89, Asp108, Lys157, Asp164, Tyr264, Gly163, Tyr273, Val165, Thr301, Pro248 –109.36 –87.06 –22.31 0 Asn109, Thr158, Gly160, Gln269,Glu161, Leu162, Val159,His89
T521 25344-25346 Sentence denotes 7.
T522 25348-25721 Sentence denotes Viscosalactone B –9.02 243.41 nM Ser85, Ala86, His89, Va159, Gly160, Asp108, Asn109, Gln269, Leu162,Glu161 –9.7 70.23 nM Lys92, His89, Val159, Trp93, Asp108, Leu162, Gly163, Tyr273, Tyr264, Pro248, Pro247, Thr301, Asp164, Lys105, Glu167, Trp106, Ala107, Glu161, Lys157 –102.08 –86.12 –15.96 0 Leu162, Glu161, Gly160, Val159, Thr158,Asn109, Asp108, Ala107, Trp106
T523 25722-25724 Sentence denotes 8.
T524 25726-25984 Sentence denotes Anaferine –6.43 19.24 µM Gly160, Asp108, Ala107, Trp93, Leu162, Glu161, Lys157 –6.0 39.69 µM Thr301, Tyr273, Tyr264, Trp106, Asp164, Pro248, Pro247, Met208, Arg166 –75.28 –68.35 –6.93 0 Ala68, Thr74, Phe79, Asp76, Pro77, Lys43, Arg65, Pro59, Leu58
T525 25985-25987 Sentence denotes 9.
T526 25989-26223 Sentence denotes Withasomnine –5.56 84.41 µM Asn109, Gln269, Cys270, Leu162, Gly160, Cys270 –7.2 4.50 µM Asp76, Pro59, Phe79, Leu80, Thr74, Ala68, Thr75, Arg65, Pro77, Leu58 –69.24 –69.24 0 0 Asp76, Pro77, Thr75, Leu80, Leu58, Pro59, Arg65
T527 26224-26227 Sentence denotes 10.
T528 26229-26477 Sentence denotes Procainamide –5.03 206.96 µM Glu161, Asn109, Leu162, Asp108, Gly160, Gln269, Cys270 –6.3 24.06 µM Asn109, Gln269, Leu162, Val159, His89, Asp108, Glu161, Gly160 –76.81 –66.66 –10.15 0 Leu162, Glu161, Gly160, Gln269,Asp108, Asn109,Cys270
T529 26478-26481 Sentence denotes 11.
T530 26483-26739 Sentence denotes Cinacalcet –6.44 19.17 µM Val159, Asp108, Gly160, Glu161, Leu162, His89, Val159 –8.8 344.50 nM Gly160, Asn109, Leu162, Gln269, Cys270, Glu161, Asp108 –81.40 –81.40 0 0 Thr158, Leu162, Glu161, Gly160, His89, Ser85, Ala86, Asn109, Val159, Asn108
T531 26740-26748 Sentence denotes Table 9.
T532 26750-26835 Sentence denotes Binding energies of WS phytoconstituents with SARS–CoV main protease/3CL-pro (PBB ID:
T533 26836-26929 Sentence denotes 1P9U) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib).
T534 26930-26981 Sentence denotes     AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T535 26982-26984 Sentence denotes S.
T536 26985-26988 Sentence denotes No.
T537 26990-27140 Sentence denotes Ligands BE (kcal/mol) K d Interacting amino acids BE(kcal/mol) K d Interacting amino acids TE(kcal/mol) VDW HB EI Interacting amino acids
T538 27141-27143 Sentence denotes 1.
T539 27145-27527 Sentence denotes Withaferin A –7.56 2.87 µM Thr47, Leu164, Pro188, Gln187, Glu165, Ser189, Met190, Gln191, Leu192, Asn168, Gly167, Leu166 –9.4 129.60 nM Gly126, Leu3, Cys284, Glu286, Arg4, Phe287, Lys5, Tyr280, Ser282, Ser279, Lys136 –116.60 –96.85 –19.75 0 Thr288, Thr290, Glu291, Arg294, Val299, Thr143, Tyr117, Cys116, Gly122, Ala115, Ser123, Gln8, Val150, Leu151, Glu152, Met6, Ser110
T540 27528-27530 Sentence denotes 2.
T541 27532-27854 Sentence denotes Withanolide A –8.93 285.01 nM Gly182, Gly183, Tyr184, Glu185, Leu192, Gln191, Met190, Ser189, Gln187, Val50 –10.9 345 nM Leu3, Arg4, Glu286, Tyr280, Phe287, Lys5, Cys284, Lys136, Ser279 –100.1 –84.54 –15.56 0 Phe272, Gly271, Leu268, Lys270, Asn269, Ser282, Leu283, Cys284, Asp285, Glu286, Lys136, Met198, Asn196
T542 27855-27857 Sentence denotes 3.
T543 27859-28194 Sentence denotes Withanolide B –8.12 1.12 µM Glu185, Gly183, Gly182, Tyr184, Ser189, Met190, Gln191, Leu192 –9.7 72.23 nM Lys270, Arg267, Leu268, Trp217, Phe218, Arg275, Gln256, Arg216, Thr254, Gly214 –104.12 –93.39 –10.74 0 Gly154, Asn153, Leu151, Glu152, Gly122, Tyr117, Ser123, Ala115, Thr143, Met6, Ser138, Ile140, Gln295, Arg294, Gly298
T544 28195-28197 Sentence denotes 4.
T545 28199-28548 Sentence denotes Withanolide D –7.68 2.34 µM Gly182, Tyr184, Glu185, Ser189, Met190, Gln191, Leu192, Glu193 –9.3 145.58 nM Glu54, Asn52, Tyr53, Arg40, Tyr81, Met57, Gln132, Ser131, Arg80, Val197, Thr239, Gly83 –111.44 –98.83 –12.61 0 Gly154, Asn153, Leu151, Glu152, Gln8, Gly122, Ser123,Cys116, Tyr117, Ala115, Thr143, Ile140, Ser138, Gln295, Met6, Arg294
T546 28549-28551 Sentence denotes 5.
T547 28553-28904 Sentence denotes Withanolide E –7.72 2.19 µM Glu185, Tyr184, Gly182, Gln132, Glu193, Gly194, Leu192, Gln191, Met190, Ser189 –9.0 240.98 nM Lys82, Gly83, Lys234, Ser131, Gln132, Ala107, Glu54, Tyr81, Arg80, Met57, Val197, Arg40, Thr239, Glu240 –104.61 –85.73 –18.88 0 Met6, Asn112, Ser110, Gln8, Val150, Glu152, Glu109, Thr288, Glu291, Gln295, Thr290, Arg294
T548 28905-28907 Sentence denotes 6.
T549 28909-29260 Sentence denotes Withanone –7.41 3.7 µM Glu193, Leu192, Gln191, Met190, Ser189, Glu185, Tyr184, Gly183, Gly182, Gln132 –9.1 212.78 nM Thr254, Arg216, Trp217, Arg275, Phe218, Lys260, Gln256, Leu268, Arg267, Lys270 –109.22 –100.63 –8.59 0 Arg294, Gln295, Ile140, Glu291, Glu152, Gly122, Ala115, Ser123, Met6, Gln8, Ala7, Ser110, Phe111, Val150, Asn112, Tyr149
T550 29261-29263 Sentence denotes 7.
T551 29265-29624 Sentence denotes Viscosalactone B –7.34 4.14 µM Leu192, Gly167, Leu166, Glu165, Leu164, Gln191, Met190, Ser189, Pro188, Gln187 –9.5 107.69 nM Lys5, Phe287, Glu286, Lys136, Met198, Asp285, Cys284, Leu283, Ser282, Arg4, Leu278, Ser279, Tyr280, Leu3 –100.67 –85.43 –15.24 0 Tyr125, Met6, Gly126, Lys5, Arg4, Leu3, Lys136, Leu278, Ser279, Tyr280, Cys284, Glu286, Phe287
T552 29625-29627 Sentence denotes 8.
T553 29629-29891 Sentence denotes Anaferine –6.19 29.14 µM Gly183, Glu185, Tyr184, Gly182, Gln191, Leu192, Glu193, Gln132 –6.8 10.34 µM Arg294, Gln295, Glu291, Gln8, Ser110, Lys5, Gly126, Ala7, Met6, Ser123, Gly122 –74.07 –60.38 –13.68 0 Tyr280, Leu3, Arg4, Lys5,Gly126, Tyr125, Val124
T554 29892-29894 Sentence denotes 9.
T555 29896-30207 Sentence denotes Withasomnine –6.06 36.09 µM Tyr53, Ile51, Ser189, Gln191, Gln187, Pro188, Asp186, Thr47, His41, Leu164, Glu165 –7.1 6.20 µM Arg294, Met6, Gln295, Glu291, Lys5, Asn112, Phe111, Gln8, Val150, Ser110, Leu151 –71.58 –63.14 –8.44 0 Ala79, Val60, Gly194, Met57, Ser58, Glu193, Gln132, Val197, Arg80, Thr195
T556 30208-30211 Sentence denotes 10.
T557 30213-30542 Sentence denotes Oberadilol –4.54 469.45 µM Glu185, Tyr184, Gly183, Gly182, Gln132, Glu193, Leu192, Gln191, Met190, Ser189 –8.7 401.24 nM Glu54, Tyr53, Arg40, Gly83, Val197, Arg80, Ser131, Thr239, Ala107, Glu240, Lys234, Lys82, Tyr81 –95.18 –81.58 –13.60 0 Trp217, Arg267, Leu268, Lys270, Phe272, Gly271, Gly273, Gly274, Arg275, Val219
T558 30543-30546 Sentence denotes 11.
T559 30548-30897 Sentence denotes Poziotinib –6.41 20.18 µM Thr195, Gly194, Glu193, Leu192, Gln191, Met159, Tyr184, Gly182, Gln132 –8.4 710.54 nM Met190, Gly167, Leu166, Ser189, Glu165, Ala141, Ile140, Phe139, Cys144, Thr47, His41, Pro188, Leu164, Gln187, Gln191 –103.87 –94.39 –9.49 0 Arg275, Gly274, Gly273, Trp217, Thr220, Asn221, Gly271, Lys270, Thr222, Arg267, Leu263
T560 30898-30907 Sentence denotes Table 10.
T561 30909-30996 Sentence denotes Binding energies of WS phytoconstituents with SARS-CoV-2 main protease/3CL-pro (PDB ID:
T562 30997-31090 Sentence denotes 6LU7) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib).
T563 31091-31142 Sentence denotes     AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T564 31143-31145 Sentence denotes S.
T565 31146-31149 Sentence denotes No.
T566 31151-31302 Sentence denotes Ligands BE (kcal/mol) K d Interacting amino acids BE(kcal/mol) Kd Interacting amino acids TE(kcal/mol) VDW HB EI Interacting amino acids  
T567 31303-31305 Sentence denotes 1.
T568 31307-31623 Sentence denotes Withaferin A –2.85 8.21 mM Tyr126, Gln127, Gly138, Va171, Gly170, Lys137, Lys5 –8.4 670.89 nM Arg105, Ile106, Val104, Ser158, Phe294,Phe112, Phe8, Thr111, Asp295, Asn151,Gln110, Thr292, Gln107 –98.51 –78.64 –19.87 0 Gly143, Ser144, Cys145, His163, Met165, Glu166, Gln189, Thr190, Asn142, Leu141, Phe140  
T569 31624-31626 Sentence denotes 2.
T570 31628-31937 Sentence denotes Withanolide A –5.26 139.0 µM Lys5, Gln127, Tyr126, Val125, Ser139, Lys137, Glu288, Glu290 –8.5 592.38 nM Asp289, Thr199, Glu290, Arg131, Lys137, Tyr239, Leu272, Leu287, Leu286, Met276, Gly275 –91.61 –70.18 –21.43 0 Gly179, Asn180, Phe181, Asn84, Cys85, Arg40, Phe185, Tyr54, Asn53, Pro52, Arg188  
T571 31938-31940 Sentence denotes 3.
T572 31942-32287 Sentence denotes Withanolide B –5.67 69.79 µM Ser139, Gly138, Lys137, Cys128, Glu290, Gln127, Tyr126, Val125 –8.3 845.65 nM Leu287, Tyr239, Tyr237, Leu272, Leu286, Asn238, Thr199, Asp289, Glu288, Arg131, Glu290, Lys137 –89.17 –72.53 –16.64 0 His163, His164, Met165, Cys145, Ser144, Phe140, Leu141, Asp142, Gly143, Thr25, Met149, Thr45, Ser46, Thr24  
T573 32288-32290 Sentence denotes 4.
T574 32292-32635 Sentence denotes Withanolide D –5.55 85.19 µM Tyr126, Gln127, Gly138, Ser139, His172, Gly170, Lys137, Lys5 –8.7 424.04 nM Tyr239, Leu287, Val204, Leu272, Tyr237, Asn238, Arg131, Lys137, Thr199, Leu286, Asp289 –104.35 –85.29 –19.06 0 Thr26, Leu27, Cys145, Gly143, Ser144, His164, Asn142, Met165, Glu166, Pro168, Thr190, Gln189, Arg188, Met49,His41  
T575 32636-32638 Sentence denotes 5.
T576 32640-32928 Sentence denotes Withanolide E –5.2 154.68 µM Tyr126, Gln127, Lys5, Glu290, Lys137, Gly138, Ser139 –8.1 1.16 µM Asn238, Asp289, Arg131, Lys137, Thr199, Leu286, Leu287, Tyr239, Leu272, Tyr237 –97.42 –70.98 –26.44 0 Arg131,Asn133, Ala194, Gly195, Asp289, Asp197, Thr196, Thr199, Thr198, Asn238  
T577 32929-32931 Sentence denotes 6.
T578 32933-33313 Sentence denotes Withanone –6.14 31.77 µM Val125, Tyr126, Gln127, Cys128, Ser139, Gly138, Lys137, Ala129, Glu290 –8.4 707.34 nM Leu286, Tyr239, Lys137, Asp197, Arg131, Thr198, Thr199, Asn238, Tyr237, Met276, Gly275, Leu272, Leu271, Leu287 –100.18 –88.69 –11.49 0 Thr24, Thr25, Thr26, His41, Gly143, Cys145, Ser144, His164, His163, His172, Phe140, Glu166, Leu141, Asn142, Met49, Ser46  
T579 33314-33316 Sentence denotes 7.
T580 33318-33690 Sentence denotes Viscosalactone B –4.86 274.4 µM Val104, Asn151, Phe8, Arg298, Gln127, Asp295, Phe294, Thr111, Thr292, Gln110, Gln107, Ile106, Arg105 –8.2 969.04 nM Gly278, Lys137, Asp289, Arg131, Tyr239, Thr199, Leu287, Leu286, Leu272, Gly275,Met276, Asn274, Asn277 –97.17 –67.45 –29.72 0 Tyr239, Asn238, Tyr237, Thr199, Leu287, Leu286, Ala285, Gly278, Asn277, Met276,Gly275  
T581 33691-33693 Sentence denotes 8.
T582 33695-34011 Sentence denotes Anaferine –5.13 174.99 µM Glu290, Cys128, Lys5, Gln127, Tyr126, Lys137 –5.7 66.02 µM Cys145, Asn142, Leu141, Phe140,Glu166, Ser144,His172,Met165, His164, Gln189, Asp187, Arg188, Met49, His41 –76.27 –67.75 –8.52 0 Thr25, Thr26, Leu27, Cys145, His163, Met165, Glu166,His172, Phe140, Leu141,Ser144, Gly143  
T583 34012-34014 Sentence denotes 9.
T584 34016-34312 Sentence denotes Withasomnine –5.22 149.2 µM Ser158, Ile152, Asp153, Asn151, Thr111, Asp295, Phe294, Thr292, Gln110 –6.2 28.68 µM Ile152, Phe8, Val104, Ile106, Gln110, Thr111, Asn151, Asp153, Phe294 –71.96 –60.03 –11.94 0 His41, His163, His164, Met165, Cys145, Ser144, His172, Glu166, Phe140, Leu141  
T585 34313-34316 Sentence denotes 10.
T586 34318-34642 Sentence denotes Oberadilol –2.23 23.18 mM Lys137, Glu290, Gln127, Tyr126, Lys5 –6.9 9.00 µM Leu286, Tyr239, Lys137, Asp197, Arg131, Thr198, Thr199, Asn238, Tyr237, Met276, Gly275, Leu272, Leu271, Leu287 –100.96 –94.41 –6.55 0 His163, Cys145, His164, Met165, Asn142, Glu166, Leu141, Leu167, Pro168, Gln189, Met49, Asp187, His41  
T587 34643-34646 Sentence denotes 11.
T588 34648-35022 Sentence denotes Poziotinib –4.49 513.87 µM Tyr126, Gln127, Cys128, Lys5, Ala129, Glu290, Lys137, Gly138, Ser139 7.7 2.20 µM Gly278, Ala285, Gly275, Tyr237, Leu272, Asn238, Tyr239, Thr199, Asp289, Arg131, Leu286, Lys137, Leu287, Met276 –111.32 –96.66 –14.66 0 His41, Cys145, His164, Asp187, Arg188, Met165, Gln189, Glu166, Thr190, Ala191, Gln192, Pro168, Phe140, Leu141, Asn142  
T589 35023-35032 Sentence denotes Table 11.
T590 35034-35126 Sentence denotes Binding energies of WS phytoconstituents with Nsp-10/Nsp-16 complex from SARS-CoV-2 (PDB ID:
T591 35127-35226 Sentence denotes 6W75) in comparison to the FDA approved standard reference drugs (Losartan and Hydroxychloroquine).
T592 35227-35278 Sentence denotes     AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T593 35279-35281 Sentence denotes S.
T594 35282-35285 Sentence denotes No.
T595 35287-35440 Sentence denotes Ligands BE (kcal/mol) K d Interacting amino acids BE(kcal/mol) K d Interacting amino acids TE(kcal/mol) VDW HB EI Interacting amino acids  
T596 35441-35443 Sentence denotes 1.
T597 35445-35888 Sentence denotes Withaferin A –9.33 144.58 nM Asp6906, Asn7095, Ser6907, Thr6908, Leu7093, Leu6909, Val7092, Ser7089, Ser7090, Val7092 –10.0 40.98 nM Lys6968, Glu7001, Ser6999, Thr6970, Ser7000, Asn6996, Lys6844, Asn6841, Tyr6930, Gly6871, Asp6928, Pro6932, Ser6872, Met6929, Gly6869, Leu6898, Asp6897, Asn6899 –99.04 –82.04 –17 0 Tyr6828, Ser6999, Ser7000, Thr6970, Glu7001, Asn6996, Lys6844, Lys6968, Asn6841, Asp6928, Tyr6930, Gly6871, Ser6872  
T598 35889-35891 Sentence denotes 2.
T599 35893-36332 Sentence denotes Withanolide A –10.38 24.67 nM Ala6905, Asp6906, Lys4346, Ser6907, Thr6908, Leu6909, Ile6910, Ser7090, Leu7093, Val7092, Ser7090 –10.4 23.67 nM Pro6932, Tyr6930, Asn6899, Asp6931, Leu6898, Asp6897, Met6929, Gly6869, Ser6872, Gly6871, Asn6841, Lys6844, Lys6968, Glu7001, Thr6970, Ser6999 –101.39 –78.76 –22.63 0 Gly6871, Gly6869, Asn6899, Asp6897, Leu6898, Asp6912, Cys6913, Phe6947, Asp6931, Lys6933, Pro6932, Met6929, Asp6928  
T600 36333-36335 Sentence denotes 3.
T601 36337-36782 Sentence denotes Withanolide B –10.09 39.9 nM Lys4346, Cys4330, His4333, Val6902, Ser6903, Phe6901, Asp6900, Thr6908, Ile6910, Leu6909, Val7092, Ser7090 –11.0 1.98 nM Lys6844, Asn6841, Asp6928, Lys6968, Tyr6930, Gly6871, Gly6869, Asp6931, Leu6898, Cys6913, Met6929, Phe6947, Asp6897, Asn6899, Ser6872, Pro6932 –103.08 –95.57 –7.51 0 Val4274, Ile4334, Asp4335, Ile4334, Cys4332, Arg4331, Thr4292, Ile4291, Pro4290, Gln4289, Ala4271, Phe4272, Ala4273  
T602 36783-36785 Sentence denotes 4.
T603 36787-37207 Sentence denotes Withanolide D –9.58 94.36 nM Val7092, Ser7089, Ser7090, Asp7091, Leu6909, Thr6908, Ser6907, Asp6906, Lys4346 –10.5 27.89 nM Lys6844, Asn6841, Asp6928, Ser6872, Tyr6930, Gly6871, Met6929, Gly6869, Leu6898, Asp6897, Asp6899, Pro6932, Asp6931, Lys6968, Thr6970, Glu7001, Ser6999 –110.77 –85.34 –25.43 0 Gly4341, Phe4342, Cys4343, Asp6906, Lys4346, Gly4347, Lys4348, Val4310, Arg6884, Thr6889, Gly6890, Asn7096  
T604 37208-37210 Sentence denotes 5.
T605 37212-37596 Sentence denotes Withanolide E –8.96 272.55 nM His4333, Phe6901, Val6902, Leu6909, Ser6903, Thr6908, Lys4346, Ser6907, Asp6906, Val7092 –9.8 62.56 nM His4333, Cys4332, Phe4272, Thr4292, Ile4291, Ala4271, Gln4289, Asn4293, Arg4331, Val6876, Lys6874, Gly6875, Val6902 –104.92 –92.21 –12.72 0 Tyr7020, Leu6820, Glu6821, Lys6822, Asp6942, Trp6974, Asn6941, Glu6940, Glu6971, His6972, Lys6939  
T606 37597-37599 Sentence denotes 6.
T607 37601-37961 Sentence denotes Withanone –10.17 34.9 nM Cys4330, His4333, Val6901, Asp6900, Phe6901, Thr6908, Ile6910, Leu6909, Ser7090, Val7092 –9.8 63.56 nM Val7092, Asp7091, Thr6915, Leu7093, Asp6912, Gly6911, Leu6898, Ser7089, Ile6910, Leu6909,Ser7090 –105.42 –91.03 –14.39 0 Ala4273, Cys4332, Val4274, Ile4334, Ala4276, Asp4335, Pro4337, Tyr4329, His4336, Asn4338, Pro4339  
T608 37962-37964 Sentence denotes 7.
T609 37966-38398 Sentence denotes Viscosalactone B –9.03 238.8 nM Asp6900, Leu7093, Val7092, Gly6911, Asp7091, Ser7090, Ile6910, Leu6909, Thr6908, Ser6907, Asp6906 –9.9 57.78 nM His4336, Ile4334, Asp4335, Tyr4329, Cys4330, His4333, Val6902, Ile6910, Asp6900, Val7092, Leu6909, Ser7089, Ser7090, Thr6908 –119.11 –103.53 –15.58 0 Thr4292, Ile4291, Pro4290, Gln4289, Tyr4283, Ala4271, Phe4272, Arg4331, Cys4332, Ile4334, Asp4335, Tyr4329, Val4274, Ala4273  
T610 38399-38401 Sentence denotes 8.
T611 38403-38686 Sentence denotes Anaferine –7.1 6.25 µM Asp4335, Asp6900, Phe6901, Ile6910, Thr6908 –6.3 22.67 nM Leu6819, Tyr7020, Val7021, Asp7018, Leu6820, Met6818, Arg6817 –86.35 –74.35 –12 0 Gly6911, Asp6912, Cys6913, Phe6947, Leu6898, Asp6897, Gly6871, Gly6869, Met6929, Tyr6930, Asp6928, Phe6947  
T612 38687-38689 Sentence denotes 9.
T613 38691-38962 Sentence denotes Withasomnine –6.06 36.03 µM Val7092, Asp7091, Ser7090, Ile6910, Leu6909, Ser7089 –8.0 1.23 µM Tyr7020, Leu6820, Met6818, Leu6819, Ala7024, Arg6817, Val7021, Asp7018 –74.52 –65.96 –8.56 0 Thr4292,Arg4331, Ile4291, Pro4290, Gln4289, Tyr4283, Phe4272, Ala4271,  
T614 38963-38966 Sentence denotes 10.
T615 38968-39347 Sentence denotes Losartan –6.49 17.54 µM Thr6908, Leu6909, Ile6910, Asp6900, Ser7090, Ser7089, Val7092 –8.3 780.68 nM Ala4273, Val4274, Asp4335, His4333, Ala4271, Ile4334, Pro4290, Gln4289, Thr4292, Ile4291, Cys4332, Phe4272, Arg4331, Gly6875, Lys6874, Val6876 –104.17 –75.33 –28.84 0 Gln6957, Gln6956, Glu7062, Lys6958, Lys6921, Ile7080, Leu6959, Leu6961, Tyr7009, Ile6955, His6984  
T616 39348-39351 Sentence denotes 11.
T617 39353-39797 Sentence denotes Hydroxychloroquine –4.93 244.14 µM Thr6908, Ile6910, Ser6907, Leu6909, Ser7090, Ser7089, Val7092 –6.7 11.70 µM Gly6869, Gly6871, Asn6841, Tyr6930, Pro6932, Ser6872, Asp6873, Asn6899, Asp6897,Leu6898, Met6929 –80.22 –69.44 −10.78 0 Lys6968, Asp6928, Gly6871, Gly6869, Met6929, Asp6897,A sn6899, Leu6898, Tyr6930, Pro6932, Ser6872   Withasomnine was found to bind near or at the active site of SARS-Co-V main protease 3CL-pro (PDB ID:
T618 39798-40043 Sentence denotes 1P9U; Table 9), whereas anaferine was found to interact with the active site residues Cys145, Glu166, Ser144, Met165, His163, His164, Gln189, Asp187, Arg188, Met49 and His41 present at the active site of SARS-CoV-2 main protease 3CL-pro (PDB ID:
T619 40044-40060 Sentence denotes 6LU7; Table 10).
T620 40061-40247 Sentence denotes The 3CL-pro active site has been found to be evolutionarily conserved between SARS-CoV and SARS-CoV-2 (Báez-Santos et al., 2015; Chen et al., 2020; Guy et al., 2005; Zhang et al., 2020).
T621 40248-40440 Sentence denotes In the same manner, the other seven phytoconstituents also displayed potent binding to the active site of SARS-CoV-2 3CL-pro except viscosalactone B as predicted by AutoDock vina and iGEMDOCK.
T622 40441-40511 Sentence denotes The active site residues have been written in bold in Tables 9 and 10.
T623 40512-40632 Sentence denotes As far as viral PL-pro and human ACE2 are concerned, WS phytoconstituents displayed allosteric binding to these enzymes.
T624 40633-40755 Sentence denotes On the other hand, withanolide A displayed strong binding to SARS-CoV spike glycoprotein (Table 6; BE: −9.78 kcal/mol, Kd:
T625 40756-40830 Sentence denotes 67.23 nM), SARS-CoV-2 spike glycoprotein (Table 7; BE: −7.18 kcal/mol, Kd:
T626 40831-40905 Sentence denotes 5.48 µM), SARS-CoV 3CL-pro main protease (Table 9; BE: –8.93 kcal/mol, Kd:
T627 40906-40988 Sentence denotes 285.01 nM) and SARS-CoV-2 Nsp10/Nsp-16 complex (Table 11; BE: −10.38 kcal/mol, Kd:
T628 40989-40999 Sentence denotes 24.67 nM).
T629 41000-41182 Sentence denotes Interestingly, withanolide A exhibited almost 1000× times stronger binding to SARS-CoV main protease as compared to standard reference drugs arbidol (Table 6; BE: −4.91 kcal/mol, Kd:
T630 41183-41250 Sentence denotes 251.65 µM) and hydroxychloroquine (Table 6; BE: −5.25 kcal/mol, Kd:
T631 41251-41262 Sentence denotes 142.18 µM).
T632 41263-41446 Sentence denotes The same binding profile was observed for withanolide A with respect to SARS-CoV-2 spike glycoprotein as compared to standard reference drugs arbidol (Table 7; BE: −3.14 kcal/mol, Kd:
T633 41447-41512 Sentence denotes 4.99 mM) and hydroxychloroquine (Table 7; BE: −2.48 kcal/mol, Kd:
T634 41513-41523 Sentence denotes 15.11 mM).
T635 41524-41679 Sentence denotes Withanolide A also displayed a 1000× stronger binding to Nsp-10/Nsp-16 complex from SARS-CoV-2 in comparison to losartan (Table 11; BE: −6.49 kcal/mol, Kd:
T636 41680-41747 Sentence denotes 17.54 µM) and hydroxychloroquine (Table 11; BE: −4.93 kcal/mol, Kd:
T637 41748-41758 Sentence denotes 244.14 µM)
T638 41759-41866 Sentence denotes Withanone also displayed significant binding to SARS-Cov-2 main protease (Table 10; BE: −6.14 kcal/mol, Kd:
T639 41867-41963 Sentence denotes 31.77 µM) in comparison to standard reference drug oberadilol (Table 10; BE: −2.23 kcal/mol, Kd:
T640 41964-41974 Sentence denotes 23.18 mM).
T641 41975-42142 Sentence denotes The best docking poses of the WS phytoconstituents with respect to the human ACE2 receptor and viral target proteins have been depicted in Table 12 (Tables 12.1–12.7).
T642 42143-42247 Sentence denotes Binding studies on WS constituents to unbound spike receptor-binding domain (RBD) of SARS-CoV-2 (PDB ID:
T643 42248-42441 Sentence denotes 6M0J) and binding of WS phytoconstituents with SARS-CoV-2 spike receptor-binding domain (RBD) bound with ACE2 have been provided as supplementary data files ST1, SFI, ST2 and SF2, respectively.
T644 42442-42451 Sentence denotes Table 12.
T645 42453-42542 Sentence denotes Best docking poses of human and viral target proteins with selected WS phytoconstituents.
T646 42543-42597 Sentence denotes Ligands AutoDock v4.2.6 AutoDock vina iGEMDOCK v2.1
T647 42598-42603 Sentence denotes 12.1.
T648 42604-42680 Sentence denotes Best docking poses of WS phytoconstituents with human ACE2 receptor (PDB ID:
T649 42681-42768 Sentence denotes 1O8A) in comparison to the FDA approved standard reference drugs (Arbidol and Losartan)
T650 42769-42781 Sentence denotes Withaferin A
T651 42782-42795 Sentence denotes Withanolide A
T652 42796-42809 Sentence denotes Withanolide B
T653 42810-42823 Sentence denotes Withanolide D
T654 42824-42837 Sentence denotes Withanolide E
T655 42838-42847 Sentence denotes Withanone
T656 42848-42864 Sentence denotes Viscosalactone B
T657 42865-42874 Sentence denotes Anaferine
T658 42875-42887 Sentence denotes Withasomnine
T659 42888-42895 Sentence denotes Arbidol
T660 42896-42904 Sentence denotes Losartan
T661 42905-42910 Sentence denotes 12.2.
T662 42911-42995 Sentence denotes Best docking poses of WS phytoconstituents with SARS-CoV spike glycoprotein (PDB ID:
T663 42996-43093 Sentence denotes 5WRG) in comparison to the FDA approved standard reference drugs (Arbidol and Hydroxychloroquine)
T664 43094-43106 Sentence denotes Withaferin A
T665 43107-43120 Sentence denotes Withanolide A
T666 43121-43134 Sentence denotes Withanolide B
T667 43135-43148 Sentence denotes Withanolide D
T668 43149-43162 Sentence denotes Withanolide E
T669 43163-43172 Sentence denotes Withanone
T670 43173-43189 Sentence denotes Viscosalactone B
T671 43190-43199 Sentence denotes Anaferine
T672 43200-43212 Sentence denotes Withasomnine
T673 43213-43220 Sentence denotes Arbidol
T674 43221-43239 Sentence denotes Hydroxychloroquine
T675 43240-43245 Sentence denotes 12.3.
T676 43246-43332 Sentence denotes Best docking poses of WS phytoconstituents with SARS-CoV-2 spike glycoprotein (PDB ID:
T677 43333-43426 Sentence denotes 6VXX) in comparison to FDA approved standard reference drugs (Arbidol and Hydroxychloroquine)
T678 43427-43439 Sentence denotes Withaferin A
T679 43440-43453 Sentence denotes Withanolide A
T680 43454-43467 Sentence denotes Withanolide B
T681 43468-43481 Sentence denotes Withanolide D
T682 43482-43495 Sentence denotes Withanolide E
T683 43496-43505 Sentence denotes Withanone
T684 43506-43522 Sentence denotes Viscosalactone B
T685 43523-43532 Sentence denotes Anaferine
T686 43533-43545 Sentence denotes Withasomnine
T687 43546-43553 Sentence denotes Arbidol
T688 43554-43572 Sentence denotes Hydroxychloroquine
T689 43573-43578 Sentence denotes 12.4.
T690 43579-43670 Sentence denotes Best docking poses of WS phytoconstituents with papain like protease of SARS-CoV-2 (PDB ID:
T691 43671-43765 Sentence denotes 6W9C) in comparison to the FDA approved standard reference drugs (Procainamide and Cinacalcet)
T692 43766-43778 Sentence denotes Withaferin A
T693 43779-43792 Sentence denotes Withanolide A
T694 43793-43806 Sentence denotes Withanolide B
T695 43807-43820 Sentence denotes Withanolide D
T696 43821-43834 Sentence denotes Withanolide E
T697 43835-43844 Sentence denotes Withanone
T698 43845-43861 Sentence denotes Viscosalactone B
T699 43862-43871 Sentence denotes Anaferine
T700 43872-43884 Sentence denotes Withasomnine
T701 43885-43897 Sentence denotes Procainamide
T702 43898-43908 Sentence denotes Cinacalcet
T703 43909-43914 Sentence denotes 12.5.
T704 43915-44002 Sentence denotes Best docking poses of WS phytoconstituents with SARS-CoV main protease/3CL-pro (PBB ID:
T705 44003-44095 Sentence denotes 1P9U) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib)
T706 44096-44108 Sentence denotes Withaferin A
T707 44109-44122 Sentence denotes Withanolide A
T708 44123-44136 Sentence denotes Withanolide B
T709 44137-44150 Sentence denotes Withanolide D
T710 44151-44164 Sentence denotes Withanolide E
T711 44165-44174 Sentence denotes Withanone
T712 44175-44191 Sentence denotes Viscosalactone B
T713 44192-44201 Sentence denotes Anaferine
T714 44202-44214 Sentence denotes Withasomnine
T715 44215-44225 Sentence denotes Oberadilol
T716 44226-44236 Sentence denotes Poziotinib
T717 44237-44242 Sentence denotes 12.6.
T718 44243-44332 Sentence denotes Best docking poses of WS phytoconstituents with SARS-CoV-2 main protease/3CL-pro (PDB ID:
T719 44333-44425 Sentence denotes 6LU7) in comparison to the FDA approved standard reference drugs (Oberadilol and Poziotinib)
T720 44426-44438 Sentence denotes Withaferin A
T721 44439-44452 Sentence denotes Withanolide A
T722 44453-44466 Sentence denotes Withanolide B
T723 44467-44480 Sentence denotes Withanolide D
T724 44481-44494 Sentence denotes Withanolide E
T725 44495-44504 Sentence denotes Withanone
T726 44505-44521 Sentence denotes Viscosalactone B
T727 44522-44531 Sentence denotes Anaferine
T728 44532-44544 Sentence denotes Withasomnine
T729 44545-44555 Sentence denotes Oberadilol
T730 44556-44566 Sentence denotes Poziotinib
T731 44567-44572 Sentence denotes 12.7.
T732 44573-44667 Sentence denotes Best docking poses of WS phytoconstituents with Nsp-10/Nsp-16 complex from SARS-CoV-2 (PDB ID:
T733 44668-44766 Sentence denotes 6W75) in comparison to the FDA approved standard reference drugs (Losartan and Hydroxychloroquine)
T734 44767-44779 Sentence denotes Withaferin A
T735 44780-44793 Sentence denotes Withanolide A
T736 44794-44807 Sentence denotes Withanolide B
T737 44808-44821 Sentence denotes Withanolide D
T738 44822-44835 Sentence denotes Withanolide E
T739 44836-44845 Sentence denotes Withanone
T740 44846-44862 Sentence denotes Viscosalactone B
T741 44863-44872 Sentence denotes Anaferine
T742 44873-44885 Sentence denotes Withasomnine
T743 44886-44894 Sentence denotes Losartan
T744 44895-44913 Sentence denotes Hydroxychloroquine
T745 44915-44919 Sentence denotes 3.4.
T746 44921-45033 Sentence denotes Bioavailability radar and score as parameters for analysis of pharmacokinetic properties of WS phytoconstituents
T747 45034-45158 Sentence denotes Pharmacokinetics and pharmacodynamics are two interlinked terms in drug development having a mutual influence on each other.
T748 45159-45271 Sentence denotes Bioavailability radar offers a first glimpse into the pharmaceutical properties of a prospective drug candidate.
T749 45272-45586 Sentence denotes By convention, the pink area represents the optimal biological range for each physiochemical property including lipophilicity (XLOGP3 range 0.7–5.0), size (MW range 150–500), polarity (TPSA range 20–130 Å2), solubility (log S ≤ 6), saturation (fraction of carbons in sp3 hybridization ≤0.25), and flexibility (≤9).
T750 45587-45791 Sentence denotes The Abbot Bioavailability Score62 is identical, but attempts to determine whether a compound is likely to have oral bioavailability score of at least 10% in rats and/or Caco-2 permeability (Martin, 2005).
T751 45792-45968 Sentence denotes As is evident from Figure 2A and B, all withanolides from WS exhibited a significant bioavailability radar and score as comparable to the standard reference FDA-approved drugs.
T752 45969-46172 Sentence denotes Figure 2. (A) Bioavailability radar and score prediction of WS phytoconstituents using SwissADME. (B) Bioavailability radar and score prediction of FDA–approved reference standard drugs using SwissADME.
T753 46174-46178 Sentence denotes 3.5.
T754 46180-46229 Sentence denotes Druglikeness and Bioactivity score (BAS) analysis
T755 46230-46404 Sentence denotes Biological targets of prospective drug candidates can be classified into ion channels, proteases, kinases, G-protein coupled receptors (GPCRs), nuclear receptors and enzymes.
T756 46405-46517 Sentence denotes The BAS of WS phytoconstituents was determined using web-based software Molinspiration (www.molinspiration.com).
T757 46518-46762 Sentence denotes As a general rule, it is known that if the BAS > 0.0, then the drug candidate is physiologically active; if it is in the range −5.0 to 0.0; then the drug candidate is moderately active, and if the BAS< −5.0, then the drug candidate is inactive.
T758 46763-46890 Sentence denotes It is evident from Table 13, that most of the WS phytoconstituents had positive values with respect to the following receptors.
T759 46892-46898 Sentence denotes 3.5.1.
T760 46900-46915 Sentence denotes As GPCR ligands
T761 46916-47049 Sentence denotes All WS phytoconstituents were active except withanolide E, anaferine and withasomnine which were predicted to be moderatively active.
T762 47050-47189 Sentence denotes Most of the reference drugs also had positive values for GPCR except procainamide and arbidol which were predicted to be moderately active.
T763 47191-47197 Sentence denotes 3.5.2.
T764 47199-47206 Sentence denotes As ICMs
T765 47207-47312 Sentence denotes All WS phytoconstituents had positive values except withasomnine which was found to be moderately active.
T766 47313-47502 Sentence denotes Standard reference drugs losartan, cinacalcet, hydroxychloroquine, oberadilol and poziotinib were all found to be active whereas procainamide and arbidol were found to be moderately active.
T767 47504-47510 Sentence denotes 3.5.3.
T768 47512-47518 Sentence denotes As KIs
T769 47519-47628 Sentence denotes All WS phytoconstituents displayed moderate activity except withasomnine that displayed significant activity.
T770 47629-47814 Sentence denotes Standard reference drugs losartan, hydroxychloroquine and poziotinib were found to be active whereas procainamide, cinacalcet, arbidol and oberadilol were found to be moderately active.
T771 47816-47822 Sentence denotes 3.5.4.
T772 47824-47831 Sentence denotes As NRLs
T773 47832-48008 Sentence denotes Withaferin A, withanolides A, B, D and E, withanone and viscosalactone B possessed significant BAS scores whereas anaferine and withasomnine were found to be moderately active.
T774 48009-48089 Sentence denotes All standard reference drugs were predicted to have moderate BAS scores as NRLs.
T775 48091-48097 Sentence denotes 3.5.5.
T776 48099-48105 Sentence denotes As PIs
T777 48106-48253 Sentence denotes Withaferin A, withanolides A, B, D and E, withanone and viscosalactone B had positive BAS scores indicating their potential as protease inhibitors.
T778 48254-48360 Sentence denotes On the other hand, anaferine and withasomnine were found to have moderate activity as protease inhibitors.
T779 48361-48505 Sentence denotes Interestingly, most withanolides especially withanolide B and withanolide A showed potent binding to papain like protease of SARS-CoV-2 (PDB ID:
T780 48506-48603 Sentence denotes 6W9C), SARS-CoV 3CL-pro main protease (PDB ID: IP9U) and SARS-CoV-2 Nsp10/Nsp-16 complex (PDB ID:
T781 48604-48676 Sentence denotes 6W75) thus supporting their role as potential viral protease inhibitors.
T782 48677-48903 Sentence denotes On the other hand, losartan, cinacalcet and hydroxychloroquine also displayed positive values as protease inhibitors whereas procainamide, arbidol, oberadilol and poziotinib displayed moderate potential as protease inhibitors.
T783 48905-48911 Sentence denotes 3.5.6.
T784 48913-48919 Sentence denotes As EIs
T785 48920-49169 Sentence denotes Most of the WS phytoconstituents including Withaferin A, withanolides A, B, D and E, withanone, viscosalactone B and anaferine had positive BAS scores indicating their potential as enzyme inhibitors whereas withasomnine displayed moderate potential.
T786 49170-49525 Sentence denotes This observation was further validated by the fact that most of the phytoconstituents including Withaferin A, withanolides A, B, D and E, viscosalactone B and anaferine showed potent binding to human ACE2 receptor in the nanomolar range which was about 1000× times greater than the binding of known standard reference drugs arbidol and losartan (Table 4).
T787 49526-49719 Sentence denotes This finding lends support for targeted use of withanolides from WS as SARS-CoV-2 entry blocking agents by virtue of their preferential binding to human ACE2, thereby blocking or inhibiting it.
T788 49720-49908 Sentence denotes Losartan, cinacalcet, hydroxychloroquine, oberadilol and poziotinib also displayed significant potential as enzyme inhibitors whereas procainamide and arbidol displayed moderate potential.
T789 49909-50019 Sentence denotes Druglikeness of a compound can be predicted by comparing its structural features with those of marketed drugs.
T790 50020-50155 Sentence denotes All WS phytoconstituents showed molar lipophilicity (cLog P) <5 thereby indicating good permeability across cell membranes (Figure 2A).
T791 50156-50345 Sentence denotes Withaferin A, withanolide D, viscosalactone B and withasomnine had positive values of druglikeness which indicated that these compounds contain fragments that are present in marketed drugs.
T792 50346-50485 Sentence denotes Out of the standard reference drugs, procainamide, hydroxychloroquine and oberadilol exhibited positive scores for druglikeness (Table 14).
T793 50486-50495 Sentence denotes Table 13.
T794 50497-50692 Sentence denotes Bioactivity scores and Druglikeness of WS phytoconstituents versus FDA-approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib).
T795 50693-50695 Sentence denotes S.
T796 50696-50699 Sentence denotes No.
T797 50701-50741 Sentence denotes Ligands Parameters of bioactivity score
T798 50742-50886 Sentence denotes GPCR ligand Ion channel modulator (ICM) Kinase inhibitor (KI) Nuclear receptor ligand (NRL) Protease inhibitor (PI) Enzymeinhibitor (EI)  
T799 50887-50912 Sentence denotes                  
T800 50913-50915 Sentence denotes 1.
T801 50917-50969 Sentence denotes Withaferin A 0.07 0.14 –0.49 0.76 0.15 0.94  
T802 50970-50972 Sentence denotes 2.
T803 50974-51027 Sentence denotes Withanolide A 0.04 0.32 –0.43 0.71 0.15 0.86  
T804 51028-51030 Sentence denotes 3.
T805 51032-51085 Sentence denotes Withanolide B 0.07 0.24 –0.47 0.79 0.15 0.76  
T806 51086-51088 Sentence denotes 4.
T807 51090-51143 Sentence denotes Withanolide D 0.05 0.30 –0.50 0.73 0.16 1.07  
T808 51144-51146 Sentence denotes 5.
T809 51148-51202 Sentence denotes Withanolide E –0.70 0.16 –0.50 0.61 0.06 0.89  
T810 51203-51205 Sentence denotes 6.
T811 51207-51256 Sentence denotes Withanone 0.00 0.27 –0.38 0.71 0.12 0.78  
T812 51257-51259 Sentence denotes 7.
T813 51261-51317 Sentence denotes Viscosalactone B 0.03 0.04 –0.51 0.78 0.19 0.84  
T814 51318-51320 Sentence denotes 8.
T815 51322-51374 Sentence denotes Anaferine –0.08 0.17 –0.60 –0.58 –0.14 0.08  
T816 51375-51377 Sentence denotes 9.
T817 51379-51435 Sentence denotes Withasomnine –0.49 –0.43 0.58 –0.10 –0.58 –0.17  
T818 51436-51439 Sentence denotes 10.
T819 51441-51488 Sentence denotes Losartan 1.06 0.16 0.03 0.01 0.33 0.44  
T820 51489-51492 Sentence denotes 11.
T821 51494-51550 Sentence denotes Procainamide –0.09 0.01 –0.10 –0.70 –0.20 –0.04  
T822 51551-51554 Sentence denotes 12.
T823 51556-51607 Sentence denotes Cinacalcet 0.22 0.15 –0.0.8 0.00 0.17 0.02  
T824 51608-51611 Sentence denotes 13.
T825 51613-51665 Sentence denotes Arbidol –0.19 –0.44 –0.39 –0.34 –0.46 –0.07  
T826 51666-51669 Sentence denotes 14.
T827 51671-51729 Sentence denotes Hydroxychloroquine 0.35 0.30 0.44 –0.12 0.12 0.15  
T828 51730-51733 Sentence denotes 15.
T829 51735-51788 Sentence denotes Oberadilol 0.04 –0.47 –0.43 –0.37 –0.02 0.02  
T830 51789-51792 Sentence denotes 16.
T831 51794-51846 Sentence denotes Poziotinib 0.04 –0.17 0.53 –0.35 –0.27 0.01  
T832 51847-51860 Sentence denotes Rule: BAS >0:
T833 51861-51868 Sentence denotes Active;
T834 51869-51882 Sentence denotes BAS –5.0–0.0:
T835 51883-51933 Sentence denotes Moderately active, moderately active and inactive.
T836 51934-51943 Sentence denotes BAS ≤5.0:
T837 51944-51953 Sentence denotes Inactive;
T838 51955-51959 Sentence denotes 3.6.
T839 51961-51985 Sentence denotes Toxicity risk assessment
T840 51986-52159 Sentence denotes In silico prediction of drug-like properties has now become a norm for pharmaceutical industries for investing in and classifying drug compounds and their product potential.
T841 52160-52336 Sentence denotes The toxicity risk evaluation is an important consideration to prevent undesirable substances with adverse effects to undergo further drug screening (Balakrishnan et al., 2015).
T842 52337-52493 Sentence denotes Potential drug candidates are analyzed for their toxicity parameters like tumorigenic, mutagenic, irritant and for their effects on the reproductive system.
T843 52494-52606 Sentence denotes In the present study, toxicity risk assessment of WS phytoconstituents was calculated using OSIRIS data warrior.
T844 52607-52815 Sentence denotes The software estimates the toxicity potential of the compounds based on similarities between the phytoconstituents being examined and the compounds present in its in vitro and in vivo database (Sander, 2001).
T845 52816-52869 Sentence denotes The obtained results have been presented in Table 15.
T846 52870-53075 Sentence denotes As is evident from Table 15, none of the analyzed WS phytoconstituents had any mutagenic effects in contrast to standard reference drugs hydroxychloroquine and poziotinib which displayed high mutagenicity.
T847 53076-53319 Sentence denotes Most of the WS phytoconstituents displayed little to no tumorigenicity in comparison to standard reference drugs cinacalcet and oberadilol which exhibited a high tendency for tumorigenicity and poziotinib which exhibited a mild tumorigenicity.
T848 53320-53623 Sentence denotes The irritant and reproductive effects of the WS phytoconstituents were also predicted to be from negligible to none, in contrast to standard reference drugs procainamide which was predicted to possess high adverse effects and poziotinib that was predicted to have mild irritant and reproductive effects.
T849 53624-53633 Sentence denotes Table 14.
T850 53635-53815 Sentence denotes Drug like properties of WS phytoconstituents versus FDA–approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib).
T851 53816-53818 Sentence denotes S.
T852 53819-53822 Sentence denotes No.
T853 53824-53860 Sentence denotes Ligands Druglikeness (DL)   clogS
T854 53861-53863 Sentence denotes 1.
T855 53865-53893 Sentence denotes Withaferin A 1.69   –4.47
T856 53894-53896 Sentence denotes 2.
T857 53898-53928 Sentence denotes Withanolide A –0.63   –4.53
T858 53929-53931 Sentence denotes 3.
T859 53933-53963 Sentence denotes Withanolide B –1.04   –4.98
T860 53964-53966 Sentence denotes 4.
T861 53968-53997 Sentence denotes Withanolide D 0.14   –4.53
T862 53998-54000 Sentence denotes 5.
T863 54002-54032 Sentence denotes Withanolide E –0.41   –4.03
T864 54033-54035 Sentence denotes 6.
T865 54037-54063 Sentence denotes Withanone –0.63   –4.53
T866 54064-54066 Sentence denotes 7.
T867 54068-54100 Sentence denotes Viscosalactone B 1.83   –4.29
T868 54101-54103 Sentence denotes 8.
T869 54105-54131 Sentence denotes Anaferine –0.69   –2.48
T870 54132-54134 Sentence denotes 9.
T871 54136-54164 Sentence denotes Withasomnine 4.16   –2.81
T872 54165-54168 Sentence denotes 10.
T873 54170-54195 Sentence denotes Losartan –6.63   –4.99
T874 54196-54199 Sentence denotes 11.
T875 54201-54229 Sentence denotes Procainamide 7.96   –1.72
T876 54230-54233 Sentence denotes 12.
T877 54235-54262 Sentence denotes Cinacalcet –4.58   –5.65
T878 54263-54266 Sentence denotes 13.
T879 54268-54292 Sentence denotes Arbidol –1.16   –4.75
T880 54293-54296 Sentence denotes 14.
T881 54298-54332 Sentence denotes Hydroxychloroquine 5.73   –3.55
T882 54333-54336 Sentence denotes 15.
T883 54338-54364 Sentence denotes Oberadilol 3.49   –6.12
T884 54365-54368 Sentence denotes 16.
T885 54370-54397 Sentence denotes Poziotinib –4.70   –6.72
T886 54399-54403 Sentence denotes 3.7.
T887 54405-54444 Sentence denotes Ligand-based target prediction analysis
T888 54445-54643 Sentence denotes Similarity in structures of ligands or distribution of electrostatic potential may result in an identical effect leading to the probability of interaction with similar targets (Wirth & Sauer, 2011).
T889 54644-54831 Sentence denotes These predictions also indicate how a drug candidate can be chemically altered in order to maximize its effect on a given target by comparing it to known ligands having similar structure.
T890 54832-54927 Sentence denotes Thus, this prediction analysis can help harness natural ligands for use as therapeutic adducts.
T891 54928-55100 Sentence denotes From the pie-chart representation, it is evident that most of the withanolides possessed broad-spectrum of bioactivity against several targets present in humans (Figure 3).
T892 55101-55110 Sentence denotes Figure 3.
T893 55112-55339 Sentence denotes Ligand–based target prediction analysis of WS phytoconstituents versus FDA–approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib) using SwissTargetPrediction.
T894 55341-55345 Sentence denotes 3.8.
T895 55347-55393 Sentence denotes Identification of SOMs in WS phytoconstituents
T896 55394-55542 Sentence denotes Biotransformation refers to a biochemical modification process of xenobiotics inside the living system involving the utilization of special enzymes.
T897 55543-55616 Sentence denotes In pharmaceutical industry, this term is equivalent to ‘drug metabolism’.
T898 55617-55819 Sentence denotes Drug metabolism influences drug-like properties of prospective drug molecules which may contribute to the production of metabolites with drastically altered pharmacological and toxicological parameters.
T899 55820-56011 Sentence denotes The recognition of SOMs containing specific atom(s) in the molecule which are oxidized by CYP isozymes, provides knowledge for the design and optimization of potent candidates in early stage.
T900 56012-56121 Sentence denotes Cytochrome P450s are accountable for more than 90% of the pharmaceutical drugs to undergo phase I metabolism.
T901 56122-56280 Sentence denotes Therefore, having prior knowledge about the metabolic liabilities of prospective drug candidates could have important ramifications in drug discovery process.
T902 56281-56439 Sentence denotes The primary, secondary and tertiary predicted SOMs for selected WS phytoconstituents versus FDA-approved standard reference drugs have been shown in Figure 4.
T903 56440-56531 Sentence denotes The figure is a graphical output for a combination of all nine isozymes of cytochrome P450.
T904 56532-56677 Sentence denotes The results indicated that WS phytoconstituents and standard reference drugs were predicted to possess SOMs likely to undergo phase I metabolism.
T905 56678-56687 Sentence denotes Figure 4.
T906 56689-56914 Sentence denotes Prediction of cytochrome P450–mediated SOMs on WS phytoconstituents versus FDA–approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib) using RS–WebPredictor.
T907 56916-56920 Sentence denotes 3.9.
T908 56922-56959 Sentence denotes Structure activity relationship (SAR)
T909 56960-57096 Sentence denotes WS is known to harbor a wide variety of secondary metabolites having low MWs viz. terpenoids, flavonoids, tannins, alkaloids and resins.
T910 57097-57275 Sentence denotes Withanolides, alkaloids, flavonoids and tannins are the major chemical constituents that include compounds of diverse chemical structures (Dhar et al., 2015; Kumar et al., 2015).
T911 57276-57366 Sentence denotes Of these, withanolides are attributed with diverse and widely known biological activities.
T912 57367-57645 Sentence denotes In the present study, most of the predicted pharmacological activity against the chosen biological target(s) was found to be associated with two main withanolides, viz. withanolide A and B, as well as withanone, a WS phytoconstituent with structural similarity to withanolide D.
T913 57646-57922 Sentence denotes Nearly 40 naturally occurring withanolides have been reported till date comprising of C-28 steroidal lactone triterpenoids assembled on an integral or reorganized ergostane structure, in which C-22 and C-26 are oxidized to form a six-membered lactone ring (Jain et al., 2012).
T914 57923-58049 Sentence denotes The withanolide backbone is chemically classified as 22-hydroxy ergostane-26-oic acid 26, 22-lactone (Mirjalili et al., 2009).
T915 58050-58188 Sentence denotes The withanolides consist of several oxygen atoms and are thought to be synthesized via oxidation of all carbon atoms in a steroid nucleus.
T916 58189-58346 Sentence denotes The parent configuration of withanolides and ergostane-type steroids is one C-8 or C-9 side chain with an either six or five membered lactone or lactol ring.
T917 58347-58497 Sentence denotes A carbon-carbon bond or oxygen bridge is responsible in attaching the lactone ring with the carbocyclic part of the molecule (Mirjalili et al., 2009).
T918 58498-58641 Sentence denotes Withanolides have a varying distribution in the fruits and vegetative parts of the plant such as leaves, roots and stem (Sangwan et al., 2008).
T919 58642-58799 Sentence denotes However, withanolides are mainly localized in the leaves, in low concentrations (0.001–0.5% of dry weight) which is the main drawback for their use as drugs.
T920 58800-58972 Sentence denotes Geographical, environmental and seasonal factors as well as growth conditions are also known to contribute to modulation of the content of withanolides (Dhar et al., 2013).
T921 58973-59307 Sentence denotes In the present study, the differential binding kinetics obtained for withanolide A (C28H38O6), withanolide B (C28H38O5), withanolide E (C28H38O7) and withanone (C28H38O7) might be attributed to the varying number of oxygen atoms in their structures which might affect hydrogen bonding within the binding site of the target protein(s).
T922 59308-59738 Sentence denotes Another explanation for differential SAR obtained for the above withanolides might be due to various kinds of structural rearrangements (A or B) involving oxygen substituents like bond scission, new bond formation, ring aromatization, etc. which help in formation of novel structural variants and compounds with novel structures (Figure 5) often described as modified withanolides or ergostane type steroids (Misico et al., 2011).
T923 59739-59922 Sentence denotes The structural rearrangement as seen in withanolide A and B might be responsible for a better complementary fit of the phytoconstituent in the binding pocket of the target protein(s).
T924 59923-59932 Sentence denotes Figure 5.
T925 59934-60093 Sentence denotes Structural differences in Withanolide A (R1 = OH, R2 = H); Withanolide B (R1 = H, R2 = H); Withanolide E (5β, 6β–epoxy) and Withanone (17α–OH, R1 = H, R2 = H).
T926 60095-60100 Sentence denotes 3.10.
T927 60102-60130 Sentence denotes Principle component analysis
T928 60131-60309 Sentence denotes PCA is one of the most familiar methods of multivariate analysis which attempts to model the total variance of originally formed data set with the unrelated principal components.
T929 60310-60527 Sentence denotes Absorption rate, TPSA, MW, clog P, NOHNH, NON, number of rotatable bonds and Lipinski’s violations were the various variable properties on which PCA was performed using linear correlation as shown in Figure 6A and 6B.
T930 60528-60708 Sentence denotes PCA analysis was also performed on leadlikeness (Table 14; Figure 7) as well as for bioactivity score parameters using linear correlation between the variables (Table 13; Figure 8)
T931 60709-60718 Sentence denotes Figure 6.
T932 60720-60947 Sentence denotes PCA of physiological properties of WS phytoconstituents versus FDA–approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib). (A) Scatter Plot (B) 3D Point Plot.
T933 60948-60957 Sentence denotes Figure 7.
T934 60959-61174 Sentence denotes PCA of leadlikeness of WS phytoconstituents versus FDA–approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib). (A) Scatter Plot (B) 3D Point Plot.
T935 61175-61184 Sentence denotes Figure 8.
T936 61186-61418 Sentence denotes PCA of bioactivity score prediction of WS phytoconstituents versus FDA– approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib). (A) Scatter Plot (B) 3D Point Plot.
T937 61419-61428 Sentence denotes Table 15.
T938 61430-61614 Sentence denotes Toxicity risk assessment of WS phytoconstituents versus FDA-approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib).
T939 61615-61617 Sentence denotes S.
T940 61618-61621 Sentence denotes No.
T941 61623-61688 Sentence denotes Ligands Mutagenic Tumorigenic Reproductive effective Irritant
T942 61689-61691 Sentence denotes 1.
T943 61693-61729 Sentence denotes Withaferin A None None Mild None
T944 61730-61732 Sentence denotes 2.
T945 61734-61771 Sentence denotes Withanolide A None Mild Mild Mild
T946 61772-61774 Sentence denotes 3.
T947 61776-61813 Sentence denotes Withanolide B None Mild Mild Mild
T948 61814-61816 Sentence denotes 4.
T949 61818-61855 Sentence denotes Withanolide D None None Mild None
T950 61856-61858 Sentence denotes 5.
T951 61860-61897 Sentence denotes Withanolide E None None Mild None
T952 61898-61900 Sentence denotes 6.
T953 61902-61935 Sentence denotes Withanone None Mild Mild Mild
T954 61936-61938 Sentence denotes 7.
T955 61940-61980 Sentence denotes Viscosalactone B None None None None
T956 61981-61983 Sentence denotes 8.
T957 61985-62018 Sentence denotes Anaferine None None None None
T958 62019-62021 Sentence denotes 9.
T959 62023-62059 Sentence denotes Withasomnine None None None None
T960 62060-62063 Sentence denotes 10.
T961 62065-62097 Sentence denotes Losartan None None None None
T962 62098-62101 Sentence denotes 11.
T963 62103-62139 Sentence denotes Procainamide None None None High
T964 62140-62143 Sentence denotes 12.
T965 62145-62179 Sentence denotes Cinacalcet None High None None
T966 62180-62183 Sentence denotes 13.
T967 62185-62216 Sentence denotes Arbidol None None None None
T968 62217-62220 Sentence denotes 14.
T969 62222-62264 Sentence denotes Hydroxychloroquine High None None None
T970 62265-62268 Sentence denotes 15.
T971 62270-62304 Sentence denotes Oberadilol None High None None
T972 62305-62308 Sentence denotes 16.
T973 62310-62523 Sentence denotes Poziotinib High Mild Mild Mild As is evident from Figures 6–8, all WS phytoconstituents fall close in 3D to the standard reference drugs used in the present study, thereby denoting their ‘drug-like’ character.
T974 62524-62678 Sentence denotes Tables 16, 17 and 18 represent the Bravais–Pearson (linear correlation) coefficients of WS phytoconstituents versus FDA-approved standard reference drugs.
T975 62679-62688 Sentence denotes Table 16.
T976 62690-62929 Sentence denotes Bravais–Pearson (linear correlation) coefficient of WS phytoconstituents versus FDA-approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib) for physicochemical properties.
T977 62930-62998 Sentence denotes Properties   1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
T978 62999-63125 Sentence denotes % AB 1   –0.719 –0.867 0.387 –0.807 0.0443 –1 0.274 0.99 –0.0259 0.037 –0.0781 0.0966 –0.0537 0.0186 5.38E–05
T979 63126-63254 Sentence denotes (NOHNH) 2 –0.719   0.582 –0.357 0.399 0.243 0.719 –0.466 –0.779 0.214 0.45 –0.346 0.156 0.032 –0.0146 –1.39E–08
T980 63255-63387 Sentence denotes (NON) 3 –0.867 0.582   0.0762 0.938 –0.0124 0.867 0.11 –0.893 –0.397 –0.147 –0.119 –0.00919 –0.0307 0.0873 2.76E–09
T981 63388-63516 Sentence denotes LV 4 0.387 –0.357 0.0762   0.0607 0.182 –0.387 0.76 0.35 –0.822 –0.0907 –0.427 –0.103 –0.00279 –0.0306 1.09E–08
T982 63517-63643 Sentence denotes MW 5 –0.807 0.399 0.938 0.0607   0.012 0.807 0.278 –0.821 –0.491 –0.203 0.157 0.0848 –0.0985 –0.0469 5.89E–10
T983 63644-63773 Sentence denotes RB 6 0.0443 0.243 –0.0124 0.182 0.012   –0.0443 0.363 0.0185 –0.386 0.905 0.157 –0.0754 –0.0364 0.00653 4.45E–09
T984 63774-63902 Sentence denotes TPSA 7 –1 0.719 0.867 –0.387 0.807 –0.0443   –0.274 –0.99 0.0259 –0.0371 0.0782 –0.0964 0.0537 –0.0186 5.38E–05
T985 63903-64031 Sentence denotes clog Pc 8 0.274 –0.466 0.11 0.76 0.278 0.363 –0.274   0.264 –0.931 –0.0242 0.205 0.112 0.0929 0.00734 –1.71E–08
T986 64032-64172 Sentence denotes pc1 9 0.99 –0.779 –0.893 0.35 –0.821 0.0185 –0.99 0.264   9.62E–09 –8.89E–09 5.33E–09 –1.73E–08 6.60E–09 –5.23E–09 1.16E–08
T987 64173-64322 Sentence denotes pc2 10 –0.0259 0.214 –0.397 –0.822 –0.491 –0.386 0.0259 –0.931 9.62E–09   –5.16E–09 –9.75E–09 –1.46E–08 –1.70E–09 3.02E–10 –8.98E–10
T988 64323-64472 Sentence denotes pc3 11 0.037 0.45 –0.147 –0.0907 –0.203 0.905 –0.0371 –0.0242 –8.89E–09 –5.16E–09   1.02E–08 –8.09E–09 –2.00E–09 –2.34E–08 –1.94E–08
T989 64473-64618 Sentence denotes pc4 12 –0.0781 –0.346 –0.119 –0.427 0.157 0.157 0.0782 0.205 5.33E–09 –9.75E–09 1.02E–08   –7.30E–09 9.18E–09 –6.69E–09 5.02E–09
T990 64619-64769 Sentence denotes pc5 13 0.0966 0.156 –0.00919 –0.103 0.0848 –0.0754 –0.0964 0.112 –1.73E–08 –1.46E–08 –8.09E–09 –7.30E–09   4.55E–09 9.35E–09 2.03E–09
T991 64770-64922 Sentence denotes pc6 14 –0.0537 0.032 –0.0307 –0.00279 –0.0985 –0.0364 0.0537 0.0929 6.60E–09 –1.70E–09 –2.00E–09 9.18E–09 4.55E–09   6.33E–09 –1.14E–08
T992 64923-65077 Sentence denotes pc7 15 0.0186 –0.0146 0.0873 –0.0306 –0.0469 0.00653 –0.0186 0.00734 –5.23E–09 3.02E–10 –2.34E–08 –6.69E–09 9.35E–09 6.33E–09   –1.39E–08
T993 65078-65244 Sentence denotes pc8 16 5.38E–05 –1.39E–08 2.76E–09 1.09E–08 5.89E–10 4.45E–09 5.38E–05 –1.71E–08 1.16E–08 –8.98E–10 –1.94E–08 5.02E–09 2.03E–09 –1.14E–08 –1.39E–08  
T994 65245-65254 Sentence denotes Table 17.
T995 65256-65506 Sentence denotes Bravais–Pearson (linear correlation) coefficient of WS phytoconstituents versus FDA–approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib) for drug like properties and leadlikeness.
T996 65507-65538 Sentence denotes Properties   1 2 3 4 5 6
T997 65539-65584 Sentence denotes LL 1   –0.669 0.631 0.858 –0.51 –0.066
T998 65585-65638 Sentence denotes clog Pc 2 –0.669   –0.754 –0.912 –0.173 –0.372
T999 65639-65687 Sentence denotes clogS 3 0.631 –0.754   0.896 0.311 –0.316
T1000 65688-65740 Sentence denotes pc1 4 0.858 –0.912 0.896   –1.95E–09 1.70E–09
T1001 65741-65793 Sentence denotes pc2 5 –0.51 –0.173 0.311 –1.95E–09   8.57E–10
T1002 65794-65847 Sentence denotes pc3 6 –0.066 –0.372 –0.316 1.70E–09 8.57E–10  
T1003 65848-65857 Sentence denotes Table 18.
T1004 65859-66100 Sentence denotes Bravais–Pearson (linear correlation) coefficient of WS phytoconstituents versus FDA–approved standard reference drugs (Losartan, Procainamide, Cinacalcet, Arbidol, Hydroxychloroquine, Oberadilol, Poziotinib) for bioactivity score prediction.
T1005 66101-66145 Sentence denotes Properties   1 2 3 4 5 6 7 8 9 10
T1006 66146-66219 Sentence denotes EI 1   0.0219 0.658 0.923 0.689 0.901 0.37 0.114 –0.0254 0.193
T1007 66220-66299 Sentence denotes GPCR 2 0.0219   0.317 –0.0436 0.573 0.354 –0.894 0.229 –0.148 0.0199
T1008 66300-66376 Sentence denotes ICM 3 0.658 0.317   0.543 0.762 0.849 –0.13 –0.501 –0.101 –0.0238
T1009 66377-66453 Sentence denotes NRL 4 0.923 –0.0436 0.543   0.599 0.836 0.456 0.244 –0.106 –0.151
T1010 66454-66529 Sentence denotes PI 5 0.689 0.573 0.762 0.599   0.905 –0.318 0.0426 0.276 –0.0383
T1011 66530-66615 Sentence denotes pc1 6 0.901 0.354 0.849 0.836 0.905   1.08E–09 8.12E–09 –3.79E–09 1.67E–08
T1012 66616-66702 Sentence denotes pc2 7 0.37 –0.894 –0.13 0.456 –0.318 1.08E–09   7.21E–09 1.03E–09 –4.17E–09
T1013 66703-66789 Sentence denotes pc3 8 0.114 0.229 –0.501 0.244 0.0426 8.12E–09 7.21E–09   4.11E–09 3.79E–10
T1014 66790-66880 Sentence denotes pc4 9 –0.0254 –0.148 –0.101 –0.106 0.276 –3.79E–09 1.03E–09 4.11E–09   9.73E–09
T1015 66881-66973 Sentence denotes pc5 10 0.193 0.0199 –0.0238 –0.151 –0.0383 1.67E–08 –4.17E–09 3.79E–10 9.73E–09  
T1016 66975-66980 Sentence denotes 3.11.
T1017 66982-67011 Sentence denotes Molecular dynamics simulation
T1018 67012-67133 Sentence denotes Figures 9 and 10, respectively, depict molecular simulation analysis of SARS-CoV-2 spike receptor-binding domain (PDB ID:
T1019 67134-67209 Sentence denotes 6M0J) bound with withanolide A and SARS-CoV-2 papain-like protease (PDB ID:
T1020 67210-67241 Sentence denotes 6W9C) bound with withanolide B.
T1021 67242-67327 Sentence denotes Both MD simulations showed an acceptable stability profile at a temperature of 300 K.
T1022 67328-67544 Sentence denotes Root mean square deviation (RMSD) is one of the most important fundamental properties to establish protein stability and its conformation to experimental structure (Kuzmanic & Zagrovic, 2010; Laskowski et al., 1997).
T1023 67545-67747 Sentence denotes RMSD is a measure of the deviation of the 3D or tertiary structure of a protein and is applied in order to get an insight into the stability of the protein in a biological system during a MD simulation.
T1024 67748-67988 Sentence denotes SARS-CoV-2 spike receptor-binding domain-withanolide A complex displayed constant RMSDs (0.5–2.0 angstrom) of both protein side chains and Cα atoms from the initial structure (before equilibrium) throughout the 3 ns time scale (Figure 9.1).
T1025 67989-68216 Sentence denotes Similarly, SARS-CoV-2 papain-like protease-withanolide B complex also exhibited constant RMSDs (0.8–2.9 angstrom) of both protein side chains and Cα atoms from the initial structure throughout the 3 ns time scale (Figure 10.1).
T1026 68217-68330 Sentence denotes Figures 11.1–11.3 and 12.1–12.3, respectively depict MS dynamics analyses of SARS-CoV spike glycoprotein (PDB ID:
T1027 68331-68393 Sentence denotes 5WRG) with withanolide B and SARS-CoV-2 main protease (PDB ID:
T1028 68394-68419 Sentence denotes 6LU7) with withanolide A.
T1029 68420-68429 Sentence denotes Figure 9.
T1030 68431-68569 Sentence denotes Molecular simulation of SARS–CoV–2 spike receptor–binding domain bound (6M0J) with withanolide A using Playmolecule open server (Table 1).
T1031 68570-68657 Sentence denotes Figures 9.1–9.2, Tables 2–4 here corresponds to the tables of MD simulation statistics.
T1032 68658-68724 Sentence denotes RMSD values were obtained as a function of time obtained at 300 K.
T1033 68725-68773 Sentence denotes Values were calculated with the use of Cα atoms.
T1034 68774-68790 Sentence denotes Figures 9.3–9.4.
T1035 68791-68874 Sentence denotes Average RMSF values obtained as a function of amino acid sequence numbers at 300 K.
T1036 68875-68923 Sentence denotes Values were calculated with the use of Cα atoms.
T1037 68924-68934 Sentence denotes Figure 10.
T1038 68936-69046 Sentence denotes Molecular simulation of papain–like protease (6W9C–A chain) with withanolide B using Playmolecule open server.
T1039 69047-69136 Sentence denotes Figures 10.1–10.2, Tables 2–4 here corresponds to the tables of MD simulation statistics.
T1040 69137-69203 Sentence denotes RMSD values were obtained as a function of time obtained at 300 K.
T1041 69204-69252 Sentence denotes Values were calculated with the use of Cα atoms.
T1042 69253-69271 Sentence denotes Figures 10.3–10.4.
T1043 69272-69355 Sentence denotes Average RMSF values obtained as a function of amino acid sequence numbers at 300 K.
T1044 69356-69404 Sentence denotes Values were calculated with the use of Cα atoms.
T1045 69405-69417 Sentence denotes Figure 11.1.
T1046 69419-69472 Sentence denotes MD simulation of SARS–CoV spike glycoprotein (PDB ID:
T1047 69473-69752 Sentence denotes 5WRG) with withanolide B using LARMD online server. (A) Ligand–protein conformation, (B) RMSD of receptor and ligand (C) RMSD histogram of receptor (D) RMSD histogram of ligand (E) Radius of gyration—Rg value (F) Fraction of native contacts analysis of SARS-CoV–2 PL-pro (PDB ID:
T1048 69753-69960 Sentence denotes 6W9C) with withanolide B over a time frame of 4000 ps (4 ns) (G) RMSF value of each residue (H) B–factor value (changing from blue to red with increase in value) and (I) B–factor analysis of defined complex.
T1049 69961-69973 Sentence denotes Figure 11.2.
T1050 69975-70018 Sentence denotes PCA of SARS–CoV spike glycoprotein (PDB ID:
T1051 70019-70753 Sentence denotes 5WRG) with withanolide B (A) PCA results for Trajectory (B) Simple clustering in PC subspace(C) Table data showing residue–wise loadings for PC1, PC2 and PC3 and residue number at each position (D) Clustering dendogram based on PC1, PC2 and PC3 (E) Dynamical residue cross–correlation map; the correlated residues are in blue, anti–correlated residues are in red; the pairwise residues with higher correlated coefficient (>0.8) and with higher anti–correlated coefficient (≤0.4) are linked with light pink and light blue (Int_mod) (F) Residue–wise loadings for PC1, PC2 and PC3 (G) Table showing pairwise cross–correlation coefficients; higher correlated coefficient value is >0.8 and higher anti–correlated coefficient value is ≤0.4.
T1052 70754-70766 Sentence denotes Figure 11.3.
T1053 70768-70865 Sentence denotes Energy, hydrogen bond analysis and decomposition analysis of SARS–CoV spike glycoprotein (PDB ID:
T1054 70866-71258 Sentence denotes 5WRG) with withanolide B (A) MM/PB(GB)SA result consists of electrostatic energy (ELE), van der Waals contribution (VDW), total gas phase energy (GAS), non–polar and polar contributions to solvation (PBSOL/GBSOL) (B,C) Statistics of hydrogen bonds (D) energy decompose of protein–ligand complex (Kcal/mol) (E) Graphical representation of decompose result (F) Showing the heatmap of decompose.
T1055 71259-71271 Sentence denotes Figure 12.1.
T1056 71273-71323 Sentence denotes MD Simulation of SARS-CoV-2 main protease (PDB ID:
T1057 71324-71603 Sentence denotes 6LU7) with withanolide A using LARMD online server. (A) Ligand-protein conformation (B) RMSD of receptor and ligand (C) RMSD histogram of receptor (D) RMSD histogram of ligand (E) Radius of gyration- Rg value (F) Fraction of native contacts analysis of SARS-CoV-2 PL-pro (PDB ID:
T1058 71604-71811 Sentence denotes 6W9C) with withanolide A, over a time frame of 4000ps (4 ns) (G) RMSF value of each residue (H) B-factor value (changing from blue to red with increase in value) and (I) B-factor analysis of defined complex.
T1059 71812-71824 Sentence denotes Figure 12.2.
T1060 71826-71866 Sentence denotes PCA of SARS-CoV-2 main protease (PDB ID:
T1061 71867-72601 Sentence denotes 6LU7) with withanolide A (A) PCA results for trajectory (B) Simple clustering in PC subspace(C) Table data showing residue-wise loadings for PC1, PC2 and PC3 and residue number at each position (D) Clustering dendogram based on PC1, PC2 and PC3 (E) Dynamical residue cross-correlation map; the correlated residues are in blue, anti-correlated residues are in red; the pairwise residues with higher correlated coefficient (>0.8) and with higher anti-correlated coefficient (≤0.4) are linked with light pink and light blue (Int_mod) (F) Residue-wise loadings for PC1, PC2 and PC3 (G) Table showing pairwise cross-correlation coefficients; higher correlated coefficient value is >0.8 and higher anti-correlated coefficient value is ≤0.4.
T1062 72602-72614 Sentence denotes Figure 12.3.
T1063 72616-72713 Sentence denotes Energy, hydrogen bond analysis and decomposition analysis of SARS-CoV spike glycoprotein (PDB ID:
T1064 72714-73106 Sentence denotes 5WRG) with withanolide B (A) MM/PB(GB)SA result consists of electrostatic energy (ELE), van der Waals contribution (VDW), total gas phase energy (GAS), non-polar and polar contributions to solvation (PBSOL/GBSOL) (B,C) Statistics of hydrogen bonds (D) Energy decompose of protein–ligand complex (Kcal/mol) (E) Graphical representation of decompose result (F) Showing the heatmap of decompose.
T1065 73107-73203 Sentence denotes Vibrations around the equilibrium are not random, but depend on the local structure flexibility.
T1066 73204-73483 Sentence denotes In order to calculate the average fluctuation of all residues during simulations, the root mean square fluctuation (RMSF) of the Cα atoms of both target proteins were plotted from the primary structure of both proteins as a function of residue number (Kuzmanic & Zagrovic, 2010).
T1067 73484-73618 Sentence denotes The obtained patterns of RMSFs for both the proteins and ligands have been presented in Figures 11.1–11.3 and 12.1–12.3, respectively.