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PMC:7441777 / 19312-49511 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T192 0-2 Sentence denotes 3.
T193 4-26 Sentence denotes Results and discussion
T194 28-32 Sentence denotes 3.1.
T195 34-60 Sentence denotes Molecular docking analysis
T196 62-68 Sentence denotes 3.1.1.
T197 70-190 Sentence denotes The binding mode analysis and predicted binding affinity calculations of natural polyphenols against the SARS-CoV-2 RdRp
T198 191-285 Sentence denotes Herein, we investigated our natural polyphenol library against RdRp of the SARS-CoV-2 (PDB ID:
T199 286-313 Sentence denotes 6M71) by molecular docking.
T200 314-456 Sentence denotes The best conformation of the natural polyphenols was docked against the SARS-CoV-2 RdRp, and resulting binding energies are listed in Table 1.
T201 457-640 Sentence denotes Polyphenols exhibiting binding energy of −7.0 kcal/mol or lower (eight polyphenols) against RdRp of the SARS-CoV-2 are listed in Table 2 along with the ligand-amino acid interactions.
T202 641-778 Sentence denotes Control compounds, GTP and remdesivir, exhibited the binding energy of −7.9 and −7.7 kcal/mol, respectively, against the SARS-CoV-2 RdRp.
T203 779-1122 Sentence denotes Eight polyphenols displayed significantly higher binding affinity among the selected hundred natural polyphenols docked against the SARS-CoV-2 RdRp, with binding energies of TF3, TF2b, TF1, TF2a, hesperidin, EGCG, myricetin and quercetagetin as −9.9, −9.6, −9.6, −9.3, −8.8, −7.3, −7.2 and −7.0 kcal/mol, respectively (highlighted in Table 1).
T204 1123-1322 Sentence denotes Further, 2D LigPlot+ representation of RdRp and the above-mentioned eight polyphenols reveal the stable network of molecular interactions (see Table 2 and Figure S1 in the Supplementary Information).
T205 1323-1331 Sentence denotes Table 2.
T206 1333-1433 Sentence denotes Ligand-amino acid interactions of top eight scoring natural polyphenols against the SARS-CoV-2 RdRp.
T207 1434-1436 Sentence denotes S.
T208 1437-1440 Sentence denotes No.
T209 1442-1538 Sentence denotes Compound name Binding energy (kcal/mol) No. of non-covalent interactions Involved amino acids
T210 1539-1657 Sentence denotes 1 TF3 −9.9 17 W617, K551, S549, D623, R836, S814, E811, F812, C813, D761, D618, S759, Y619, C622, R553, K621, D760
T211 1658-1753 Sentence denotes 2 TF2b −9.6 13 K551, Y619, D760, K798, W617, W800, D761, F812, C813, E811, D618, S549, A550
T212 1754-1842 Sentence denotes 3 TF1 −9.6 12 W617, D761, D760, Y619, R553, K621, P620, F793, D164, S795, K798, D618
T213 1843-1944 Sentence denotes 4 TF2a −9.3 14 C813, F812, D761, D760, D618, K798, K551, A550, S549, K621, Y619, W800, W617, E811
T214 1945-2046 Sentence denotes 5 Hesperidin −8.8 13 Y619, D618, K798, S795, M794, P793, D164, V166, P620, K621, D623, R555, Y455
T215 2047-2117 Sentence denotes 6 EGCG −7.3 9 D623, Y619, K621, S795, C622, D618, M794, P620, K798
T216 2118-2200 Sentence denotes 7 Myricetin −7.2 10 W617, W800, D760, E811, K798, D618, Y619, C622, D761, F812
T217 2201-2274 Sentence denotes 8 Quercetagetin −7.0 8 R553, K545, K621, D623, C622, D760, P620, Y619
T218 2275-2386 Sentence denotes 9 Remdesivir (Control) −7.7 13 R553, K621, C622, D760, E811, W800, K798, P620, Y455, R624, Y619, D618, D761
T219 2387-2726 Sentence denotes 10 GTP (Control) −7.9 15 R624, T556, D623, D760, Y619, C622, K621, D452, A554, R553, Y455, R555, D761, D618, P620 In addition to remdesivir, here we observed that eight dietary polyphenols (TF1, TF2a, TF2b, TF3, hesperidin, EGCG, myricetin and quercetagetin) have significant potential to function as inhibitors of the SARS-CoV-2 RdRp.
T220 2727-3034 Sentence denotes The top-eight scoring ligands for the SARS-CoV-2 RdRp (as highlighted in Table 1) suggest that these set of natural polyphenols can strongly bind to the catalytic site of the SARS-CoV-2 RdRp and are expected to inhibit the RdRp activity, and thus blocking the replication and preventing viral transcription.
T221 3035-3187 Sentence denotes Many reports suggest polyphenols have low systemic toxicity, and they are highly beneficial for human health (Bhardwaj et al., 2020; Cory et al., 2018).
T222 3188-3416 Sentence denotes TF1 and its gallate derivatives, collectively known as black tea polyphenols, previously have shown to exert antiviral activity against many viruses such as hepatitis virus and influenza A and B viruses (Chowdhury et al., 2018).
T223 3417-3589 Sentence denotes Hesperidin is also known to possess antiviral activity by altering the immune system mainly via regulating interferons in the influenza A virus (Randall & Goodbourn, 2008).
T224 3590-3740 Sentence denotes EGCG, a major green tea polyphenol, has several pharmacological properties, including antiviral activity (Carneiro et al., 2016; Moon & Morris, 2007).
T225 3741-3856 Sentence denotes Similarly, myricetin has also been found to act as an inhibitor of the SARS coronavirus helicase (Yu et al., 2012).
T226 3857-3979 Sentence denotes Quercetagetin also showed strong hepatitis C virus replication inhibitory activity in vitro (Ahmed-Belkacem et al., 2014).
T227 3980-4172 Sentence denotes Thus, the set dietary polyphenols identified in the present study could be used as repurposed drugs for the treatment of the SARS-CoV-2 infection with further in-vitro and in-vivo validations.
T228 4174-4178 Sentence denotes 3.2.
T229 4180-4214 Sentence denotes Molecular dynamics (MD) simulation
T230 4216-4222 Sentence denotes 3.2.1.
T231 4224-4272 Sentence denotes Thermodynamic stability and flexibility analysis
T232 4273-4557 Sentence denotes The 150 ns production simulations carried out for nine systems (complex of remdesivir, EGCG, TF1, TF2a, TF2b, TF3, hesperidin, myricetin, and quercetagetin with the SARS-CoV-2 RdRp) were stable on the basis of the potential energy and total energy (data not shown) of those complexes.
T233 4558-4739 Sentence denotes Subsequently, the root-mean-square deviations (RMSDs) of backbone atoms relative to their respective initial positions were calculated for each complex and are shown in Figure 3(A).
T234 4740-4907 Sentence denotes It is evident from Figure 3(A) that all the nine studied systems drifted from their initial positions during the first 50 ns, and after that, they reached equilibrium.
T235 4908-5191 Sentence denotes The average RMSD values were estimated to be 2.30 Å, 2.45 Å, 1.87 Å, 2.28 Å, 1.68 Å, 2.47 Å, 1.90 Å, 2.03 Å and 1.88 Å for RdRp/remdesivir, RdRp/EGCG, RdRp/TF3, RdRp/TF2b, RdRp/TF2a, RdRp/myricetin, RdRp/quercetagetin, RdRp/hesperidin, and RdRp/TF1 complexes, respectively (Table 3).
T236 5192-5293 Sentence denotes The least deviation was observed for RdRp/TF2a, while RdRp/myricetin displayed the highest deviation.
T237 5294-5515 Sentence denotes We also investigated structural variations in the binding site, including all amino acids that fall within a radius of 5 Å from the inhibitor, and the same trend was observed (Figure S2A in the Supplementary Information).
T238 5516-5574 Sentence denotes Overall, this suggests the convergence of our simulations.
T239 5575-5798 Sentence denotes Figure 3. (A) Time evolution of root-mean-square deviations (RMSDs) of backbone atoms and (B) the root-mean-square fluctuations (RMSFs) of Cα atoms of nine complexes relative to their respective energy minimized structure.
T240 5799-5807 Sentence denotes Table 3.
T241 5809-5928 Sentence denotes The average backbone RMSD, radius of gyration (RoG), and solvent accessible surface area (SASA) for all nine complexes.
T242 5929-5997 Sentence denotes The data are reported as average ± standard error of the mean (SEM).
T243 5998-6034 Sentence denotes System RMSD (Å) RoG (Å) SASA (Å2)
T244 6035-6095 Sentence denotes RdRp/Remdesivir 2.30 ± 0.03 29.96 ± 0.02 34973.20 ± 91.56
T245 6096-6150 Sentence denotes RdRp/EGCG 2.45 ± 0.05 29.52 ± 0.06 35026.03 ± 63.52
T246 6151-6204 Sentence denotes RdRp/TF3 1.87 ± 0.02 29.60 ± 0.01 34080.16 ± 53.41
T247 6205-6259 Sentence denotes RdRp/TF2b 2.28 ± 0.01 29.86 ± 0.02 35462.92 ± 50.40
T248 6260-6315 Sentence denotes RdRp/TF2a 1.68 ± 0.02 29.75 ± 0.02 34312.55 ± 112.89
T249 6316-6376 Sentence denotes RdRp/Myricetin 2.47 ± 0.03 29.88 ± 0.01 35395.35 ± 104.67
T250 6377-6440 Sentence denotes RdRp/Quercetagetin 1.90 ± 0.03 29.84 ± 0.01 34618.65 ± 51.25
T251 6441-6501 Sentence denotes RdRp/Hesperidin 2.03 ± 0.04 29.74 ± 0.02 34554.08 ± 47.25
T252 6502-6786 Sentence denotes RdRp/TF1 1.88 ± 0.03 29.86 ± 0.01 34420.69 ± 56.90 Next, we investigated the structural stability of remdesivir and eight polyphenols by estimating the temporal RMSDs of heavy atoms relative to their respective initial coordinates (see Figure S2B in the Supplementary Information).
T253 6787-6940 Sentence denotes It is evident from Figure S2B that EGCG, myricetin, quercetagetin, TF1, TF3 displayed a rigid behavior in the bound form with an average RMSD of < 1.0 Å.
T254 6941-7103 Sentence denotes However, remdesivir, TF2a, TF2b and hesperidin showed higher fluctuations as compared to the abovementioned polyphenols, and an average RMSD of > 2.0 Å was noted.
T255 7104-7258 Sentence denotes To identify the regions which are flexible, the root-mean-square fluctuations (RMSFs) of Cα atoms of each residue are calculated and shown in Figure 3(B).
T256 7259-7430 Sentence denotes From this analysis, we can get a better insight into what extent the binding of remdesivir and natural polyphenols affects the residual flexibility of RdRp (mainly Nsp12).
T257 7431-7525 Sentence denotes Figure 3(B) indicates that RdRp/remdesivir and RdRp-polyphenols shared a similar RMSF pattern.
T258 7526-7641 Sentence denotes Notable dynamic fluctuations were located in the non-active site domain, including both N-terminals and C-terminal.
T259 7642-7775 Sentence denotes Regions around Asn150, Asp260, Arg305, Asn360, and Phe440 are found to be more flexible compared to the other area for all complexes.
T260 7776-8100 Sentence denotes The binding pocket residues, such as Asp452, Lys545, Lys551, Tyr455, Arg553, Ala554, Arg555, Thr556, Asp618, Tyr619, pro620, Lys621, Cys622, Asp623 Arg624, Asn691, Asp760, Asp761, Phe793, Met794, Ser795, Lys798, Trp800, Glu811, Phe812, and Ser814 exhibited considerably low fluctuations for all the RdRp-inhibitor complexes.
T261 8101-8244 Sentence denotes In the case of RdRp/TF3 and RdRp/TF2a, the binding site residues displayed lesser fluctuations compared to the other RdRp-polyphenol complexes.
T262 8245-8349 Sentence denotes This suggests that TF3 and TF2a are likely to be bound to RdRp more strongly than the other polyphenols.
T263 8350-8541 Sentence denotes Since the radius of gyration (RoG) helps us to understand the protein structural compactness, RoG of each complex was monitored and represented in Figure S3A in the Supplementary Information.
T264 8542-8782 Sentence denotes The average values of RoG are 29.96 Å, 29.52 Å, 29.60 Å, 29.86 Å, 29.75 Å, 29.88 Å, 29.84 Å, 29.74 Å and 29.86 Å for RdRp complexed with remdesivir, EGCG, TF3, TF2b, TF2a, myricetin, quercetagetin, hesperidin and TF1 respectively (Table 3).
T265 8783-8867 Sentence denotes This suggests that the structural compactness remained unchanged during simulations.
T266 8868-9062 Sentence denotes Finally, the solvent-accessible surface area (SASA) was also explored, and the time evolution of SASA for four RdRp-polyphenol complexes are shown in Figure S3B in the Supplementary Information.
T267 9063-9114 Sentence denotes The average values of SASA are reported in Table 3.
T268 9115-9226 Sentence denotes Binding of an inhibitor to the substrate changes SASA and sometimes could greatly affect the protein structure.
T269 9227-9351 Sentence denotes Here, a relatively higher SASA value was obtained for RdRp/TF2b (35462.9 Å2) compared to the other RdRp/inhibitor complexes.
T270 9352-9429 Sentence denotes On the other hand, the lowest SASA value was noted for RdRp/TF3 (34080.2 Å2).
T271 9430-9523 Sentence denotes Thus, it can be suggested that the binding of TF3 could potentially reduce protein expansion.
T272 9525-9531 Sentence denotes 3.2.2.
T273 9533-9561 Sentence denotes Binding free energy analysis
T274 9562-9795 Sentence denotes We predicted the binding free energy of all nine complexes by utilizing the MM-PBSA scheme, and four polyphenols, namely EGCG, TF3, TF2b, and TF2a, displayed a higher estimated affinity compared to remdesivir as depicted in Figure 4.
T275 9796-9895 Sentence denotes Various components of the binding free energy of EGCG, TF3, TF2b, and TF2a are reported in Table 4.
T276 9896-10038 Sentence denotes The remaining four polyphenols which showed lower estimated affinity compare to remdesivir are shown in Table S2 in Supplementary Information.
T277 10039-10264 Sentence denotes It can be noted from Figure 4 that the intermolecular van der Waals (ΔEvdW) and electrostatic (ΔEelec) terms are favorable for the ligand binding, whereas the desolvation of polar groups (ΔGpol) opposes the complex formation.
T278 10265-10346 Sentence denotes Non-polar solvation free energy (ΔGnp) is favorable to the binding for all cases.
T279 10347-10430 Sentence denotes A similar trend was observed in our earlier study (Sk, Roy, Jonniya, et al., 2020).
T280 10431-10440 Sentence denotes Figure 4.
T281 10442-10729 Sentence denotes Energy components (kcal/mol) for the binding of remdesivir and four polyphenols to RdRp receptor. ΔEvdW, van der Waals interaction; ΔEele, electrostatic interaction in the gas phase; ΔGpol, polar solvation energy; ΔGnp, non-polar solvation energy, and ΔGbind, estimated binding affinity.
T282 10730-10738 Sentence denotes Table 4.
T283 10740-10864 Sentence denotes Energetic components of the binding free energy of RdRp and natural polyphenols along with remdesivir complexes in kcal/mol.
T284 10865-10903 Sentence denotes Data are represented as average ± SEM.
T285 10904-10949 Sentence denotes Components Remdesivir EGCG TF3 TF2b TF2a
T286 10950-11030 Sentence denotes ΔEvdW −31.85 ± 0.15 −25.11 ± 0.18 −37.82 ± 0.21 −30.66 ± 0.23 −22.55 ± 0.19
T287 11031-11113 Sentence denotes ΔEelec −98.40 ± 0.70 −69.38 ± 0.73 −123.63 ± 0.88 −47.18 ± 0.64 −95.28 ± 1.27
T288 11114-11191 Sentence denotes ΔGpol 109.97 ± 0.57 71.62 ± 0.48 124.47 ± 0.58 55.01 ± 0.49 94.94 ± 1.10
T289 11192-11266 Sentence denotes ΔGnp −4.29 ± 0.01 −4.15 ± 0.01 −5.29 ± 0.01 −3.91 ± 0.01 −4.28 ± 0.02
T290 11267-11345 Sentence denotes aΔGsolv 105.68 ± 0.57 67.47 ± 0.48 119.18 ± 0.58 51.1 ± 0.49 90.66 ± 1.10
T291 11346-11426 Sentence denotes bΔGpol + elec 11.57 ± 0.90 2.24 ± 0.87 0.84 ± 1.05 7.83 ± 0.80 −0.34 ± 1.68
T292 11427-11510 Sentence denotes cΔEMM −130.25 ± 0.71 −94.49 ± 0.75 −161.45 ± 0.90 −77.84 ± 0.68 −117.83 ± 1.28
T293 11511-11595 Sentence denotes ΔGbindSim −24.57 ± 0.91 −27.02 ± 0.89 −42.27 ± 1.07 −26.74 ± 0.83 −27.17 ± 1.69
T294 11596-11621 Sentence denotes a ΔGsolv = ΔGnp + ΔGpol,
T295 11622-11655 Sentence denotes b ΔGpol + elec = ΔEelec + ΔGpol,
T296 11656-11681 Sentence denotes c ΔEMM = ΔEvdW + ΔEelec.
T297 11682-11851 Sentence denotes It is evident from Table 4 that for all complexes, ΔEvdW varies between −22.55 kcal/mol and −37.82 kcal/mol while ΔEelec ranges from −47.18 kcal/mol to −123.63 kcal/mol.
T298 11852-12298 Sentence denotes Furthermore, in the cases of RdRp/remdesivir, RdRp/EGCG, RdRp/TF3, and RdRp/TF2b, ΔEele is over-compensated by the desolvation energy (ΔGpol), indicating that the sum of these two components, ΔGpol + elec, is unfavorable to the binding and varies between 0.84 kcal/mol and 11.57 kcal/mol (see Table 4) and similar results are found for RdRp/myricetin, RdRp/quercetagetin, RdRp/hesperidin, and RdRp/TF1 (see Table S2 in Supplementary Information).
T299 12299-12417 Sentence denotes In contrast, in the case of RdRp/TF2a, ΔGpol + elec, is favorable to the complexation (ΔGpol + elec = −0.34 kcal/mol).
T300 12418-12570 Sentence denotes Overall, this suggests that the complex formation is mainly driven by the van der Waals interactions between polyphenols as well as remdesivir and RdRp.
T301 12571-12675 Sentence denotes Therefore, hydrophobic residues in the binding pocket played a crucial role in the complexation process.
T302 12676-12992 Sentence denotes The estimated binding free energy (ΔGbind) of remdesivir, EGCG, TF3, TF2b, and TF2a were −24.57, −27.02, −42.27, −26.74 and −27.17 kcal/mol, respectively (Table 4) and myricetin, quercetagetin, hesperidin and TF1 show lower binding affinity compared to that of remdesivir (Table S2 in the Supplementary Information).
T303 12993-13082 Sentence denotes This suggests that polyphenol TF3 binds most strongly to RdRp, followed by TF2a and EGCG.
T304 13083-13190 Sentence denotes The potency of the five inhibitors decreases in the following order: TF3 > TF2a > EGCG > TF2b > remdesivir.
T305 13191-13320 Sentence denotes TF3 binds most strongly to RdRp because both ΔEvdW and ΔEelec are more favorable to the binding compared to the other inhibitors.
T306 13321-13581 Sentence denotes Similarly, TF2a binds more strongly to RdRp compared to EGCG or TF2b because ΔGpol + elec is favorable for TF2a (ΔGpol + elec = −0.34 kcal/mol) while it is found to be unfavorable for EGCG (ΔGpol + elec = 2.24 kcal/mol) and TF2b (ΔGpol + elec = 7.83 kcal/mol).
T307 13583-13589 Sentence denotes 3.2.3.
T308 13591-13633 Sentence denotes Essential residues for polyphenols binding
T309 13634-13843 Sentence denotes Further, to gain a deeper insight into the best four RdRp/polyphenols and remdesivir interaction pattern, the total binding free energy was decomposed into polyphenols-residue pair based on the MM-GBSA scheme.
T310 13844-14034 Sentence denotes The approach of per-residue based contributions is useful to determine the binding mechanisms of an inhibitor at an atomistic level, and it also reveals the individual residue contributions.
T311 14035-14163 Sentence denotes The different energy contributions from the backbone and side-chain of each residue are shown in Figure 5 and listed in Table 5.
T312 14164-14173 Sentence denotes Figure 5.
T313 14175-14321 Sentence denotes Decomposition of the binding free energy into contributions from individual residues for RdRp complexed with remdesivir, EGCG, TF3, TF2b and TF2a.
T314 14322-14330 Sentence denotes Table 5.
T315 14332-14468 Sentence denotes Per-residue based decomposition of binding free energy for the complex of remdesivir, EGCG, TF3, TF2a and TF2b with the SARS-CoV-2 RdRp.
T316 14469-14532 Sentence denotes Residue TvdW Telec Tpol Tnp Tside_chain Tbackbone Ttotal
T317 14533-14548 Sentence denotes RdRp/Remdesivir
T318 14549-14604 Sentence denotes Asp761 1.05 −21.73 18.81 −0.14 −1.82 −0.19 −2.01
T319 14605-14658 Sentence denotes Lys798 −2.74 −4.28 5.74 −0.47 −1.76 0.01 −1.75
T320 14659-14713 Sentence denotes Pro620 −1.42 −1.15 1.16 −0.18 −1.26 −0.33 −1.59
T321 14714-14768 Sentence denotes Asp760 −0.57 −4.27 4.24 −0.12 −0.20 −0.52 −0.72
T322 14769-14822 Sentence denotes Arg553 −2.07 −3.71 5.61 −0.51 −0.76 0.08 −0.68
T323 14823-14832 Sentence denotes RdRp/EGCG
T324 14833-14886 Sentence denotes Asp452 1.65 −16.48 9.85 −0.08 −5.15 0.09 −5.06
T325 14887-14940 Sentence denotes Arg553 −3.83 −4.84 6.59 −0.59 −2.68 0.01 −2.67
T326 14941-14995 Sentence denotes Pro620 −1.64 −0.41 0.51 −0.33 −1.62 −0.25 −1.87
T327 14996-15049 Sentence denotes Asp618 0.49 −8.14 6.66 −0.09 −1.13 −0.05 −1.08
T328 15050-15104 Sentence denotes Lys621 −2.26 −5.12 6.92 −0.50 −0.87 −0.09 −0.96
T329 15105-15113 Sentence denotes RdRp/TF3
T330 15114-15169 Sentence denotes Asp761 2.52 −30.13 22.11 −0.25 −5.54 −0.21 −5.75
T331 15170-15226 Sentence denotes Arg836 −0.83 −14.95 12.29 −0.37 −3.85 −0.01 −3.86
T332 15227-15281 Sentence denotes Arg555 −5.80 −4.00 7.29 −0.70 −2.98 −0.23 −3.21
T333 15282-15336 Sentence denotes Thr556 −0.20 −3.96 2.44 −0.13 −0.21 −1.64 −1.85
T334 15337-15391 Sentence denotes Ile548 −1.03 −0.08 0.12 −0.13 −0.65 −0.47 −1.12
T335 15392-15445 Sentence denotes Ser814 −1.67 0.09 0.78 −0.08 −0.48 −0.40 −0.88
T336 15446-15500 Sentence denotes Val557 −0.65 −0.16 0.17 −0.24 −0.65 −0.23 −0.88
T337 15501-15510 Sentence denotes RdRp/TF2b
T338 15511-15565 Sentence denotes His816 −3.00 −0.81 1.69 −0.32 −1.63 −0.81 −2.44
T339 15566-15620 Sentence denotes Asp833 −1.29 −0.23 0.46 −0.18 −0.21 −1.03 −1.24
T340 15621-15675 Sentence denotes Tyr877 −0.92 −2.06 2.06 −0.27 −0.43 −0.76 −1.19
T341 15676-15728 Sentence denotes Glu811 0.22 −9.24 8.11 −0.13 −2.07 1.03 −1.04
T342 15729-15783 Sentence denotes His810 −1.88 −0.41 1.66 −0.34 −0.10 −0.85 −0.95
T343 15784-15838 Sentence denotes Tyr831 −1.51 −0.36 1.19 −0.13 −0.21 −0.60 −0.81
T344 15839-15893 Sentence denotes Asn815 −0.60 −0.27 0.09 −0.01 −0.25 −0.54 −0.79
T345 15894-15903 Sentence denotes RdRp/TF2a
T346 15904-15959 Sentence denotes Asp618 2.63 −20.71 13.40 −0.17 −4.84 −0.01 −4.85
T347 15960-16014 Sentence denotes Arg553 −3.80 −6.52 7.55 −0.69 −2.68 −0.78 −3.46
T348 16015-16069 Sentence denotes Lys551 −2.23 −0.80 2.23 −0.45 −0.84 −0.41 −1.25
T349 16070-16124 Sentence denotes Arg555 −1.33 −0.62 1.05 −0.27 −1.12 −0.05 −1.17
T350 16125-16407 Sentence denotes Glu167 0.42 −6.82 5.92 −0.12 −0.61 0.01 −0.60 As shown in Figure 5, it was observed that residues favoring the binding of the polyphenols with RdRp include Asp452, Arg553, Arg555, Val557, Asp618, Pro620, Lys621, Asp623, Arg624, Asp760, Asp761, and Glu811, Asp833, and Arg836.
T351 16408-16532 Sentence denotes Most of these residues are located in the binding site of RdRp and can form direct contacts with polyphenols and remdesivir.
T352 16533-16909 Sentence denotes Figure 5 shows that amino acids Pro620, Asp761 and Lys798 for RdRp/remdesivir; Asp452, Arg553, Pro620 and Lys621 for RdRp/EGCG; Ile548, Arg555, Thr556, Asp761 and Arg836 for RdRp/TF3; Glu811, His816, Asp833 and Tyr877 for RdRp/TF2b; Lys551, Arg553, Arg555 and Asp618 for RdRp/TF2a contributed more favorably towards the binding by contributing more than −1.0 kcal/mol in size.
T353 16910-17090 Sentence denotes To complement the energetic analysis, we performed MD trajectory-based hydrogen bond (h-bond) analysis for all five complexes, and the h-bonds with occupancy are listed in Table 6.
T354 17091-17199 Sentence denotes The h-bonds were determined by setting the acceptor-donor distance of ≤ 3.5 Å, and the angle cut off ≥ 1200.
T355 17200-17264 Sentence denotes Important h-bonds between RdRp-inhibitors are shown in Figure 6.
T356 17265-17388 Sentence denotes In the case of RdRp/remdesivir, key residues involved in the hydrogen bonding are Asp761, Asp760, and Ser759, respectively.
T357 17389-17546 Sentence denotes Asp760 is found to form two h-bonds with remdesivir (Asp760@OD2 - Lig@O7, Asp760@OD2 - Lig@O6) with an occupancy of more than 15% (see Table 6 and Figure 6).
T358 17547-17679 Sentence denotes In the case of RdRp/EGCG, both Asp618 and Asp760 form two h-bonds with the ligand with an occupancy in the range of 16.09 to 30.17%.
T359 17680-17927 Sentence denotes On the other hand, Asp761 form an h-bond with TF3 (Asp761@OD1 - Lig@O11) with an occupancy of 69.84%, while Arg836 forms two h-bonds with the ligand (Arg836@NH2 - Lig@O14, Arg836@NE - Lig@O14) with an occupancy of 52.66%, and 48.70%, respectively.
T360 17928-18080 Sentence denotes Glu811, Thr556 and Asp761 also formed h-bonds with the ligand during our simulations with an occupancy varying in the range of 44% to 58% (see Table 6).
T361 18081-18262 Sentence denotes In the case of RdRp/TF2b, Glu811 is found to form two strong h–bonds with the ligand (Glu811@OE1 – Lig@O7, Glu811@OE2 – Lig@O7) with an occupancy of 22.45% and 18.89%, respectively.
T362 18263-18432 Sentence denotes On the other hand, it can be observed from Table 6 that Pro832 and Tyr877 form strong h-bonds (Pro832@O -Lig@O8 and Lig@O10 -Tyr877@OH) with increased occupancy (> 24%).
T363 18433-18623 Sentence denotes Finally, in the case of RdRp/TF2a, Asp618 is found to form two strong h-bonds with the TF2a (Asp618@OD1 – Lig@O10, Asp618@OD1 – Lig@O11) with an occupancy of 38.68% and 38.38%, respectively.
T364 18624-18700 Sentence denotes Asp760 also forms a h-bond (Asp760@O – Lig@O11) with an occupancy of 20.83%.
T365 18701-18710 Sentence denotes Figure 6.
T366 18712-18774 Sentence denotes Five main hydrogen bond interactions between ligands and RdRp.
T367 18775-18783 Sentence denotes Table 6.
T368 18785-18998 Sentence denotes Main hydrogen bond interactions formed by RdRp with remdesivir and polyphenols along with the corresponding average distance and percentage of occupancy determined using the trajectories of production simulations.
T369 18999-19020 Sentence denotes Acceptor Donor Avg.
T370 19021-19048 Sentence denotes Distance (Å) Occupancy (%)
T371 19049-19064 Sentence denotes RdRp/Remdesivir
T372 19065-19096 Sentence denotes Asp760@OD2 Lig@O7 2.66 19.46
T373 19097-19128 Sentence denotes Asp761@OD1 Lig@O7 2.65 17.70
T374 19129-19160 Sentence denotes Asp761@OD2 Lig@O6 2.63 16.86
T375 19161-19192 Sentence denotes Asp760@OD2 Lig@O6 2.65 16.65
T376 19193-19223 Sentence denotes Lig@O6 Ser759@OG 2.80 11.63
T377 19224-19255 Sentence denotes Asp760@OD1 Lig@O7 2.66 10.59
T378 19256-19265 Sentence denotes RdRp/EGCG
T379 19266-19297 Sentence denotes Asp618@OD1 Lig@O5 2.61 30.13
T380 19298-19329 Sentence denotes Asp618@OD1 Lig@O6 2.61 29.28
T381 19330-19361 Sentence denotes Asp618@OD2 Lig@O5 2.61 18.25
T382 19362-19393 Sentence denotes Asp618@OD2 Lig@O6 2.61 17.38
T383 19394-19425 Sentence denotes Asp760@OD1 Lig@O5 2.63 16.09
T384 19426-19457 Sentence denotes Tyr455@OH Lig@O11 2.83 10.97
T385 19458-19466 Sentence denotes RdRp/TF3
T386 19467-19499 Sentence denotes Asp761@OD1 Lig@O11 2.61 69.84
T387 19500-19530 Sentence denotes Glu811@O Lig@O10 2.76 58.43
T388 19531-19560 Sentence denotes Thr556@O Lig@O3 2.72 56.95
T389 19561-19593 Sentence denotes Lig@O14 Arg836@NH2 2.83 52.66
T390 19594-19625 Sentence denotes Lig@O14 Arg836@NE 2.86 48.70
T391 19626-19658 Sentence denotes Asp761@OD2 Lig@O20 2.62 44.51
T392 19659-19668 Sentence denotes RdRp/TF2b
T393 19669-19698 Sentence denotes Pro832@O Lig@O8 2.77 26.31
T394 19699-19730 Sentence denotes Lig@O11 Tyr877@OH 2.75 24.39
T395 19731-19762 Sentence denotes Glu811@OE1 Lig@O7 2.65 22.45
T396 19763-19794 Sentence denotes Glu811@OE2 Lig@O7 2.65 18.89
T397 19795-19826 Sentence denotes Asp833@OD2 Lig@O8 2.65 12.01
T398 19827-19858 Sentence denotes Asn874@OD1 Lig@O11 2.68 8.58
T399 19859-19868 Sentence denotes RdRp/TF2a
T400 19869-19901 Sentence denotes Asp618@OD1 Lig@O10 2.59 38.68
T401 19902-19934 Sentence denotes Asp618@OD1 Lig@O11 2.62 38.38
T402 19935-19965 Sentence denotes Asp760@O Lig@O11 2.70 20.83
T403 19966-19998 Sentence denotes Asp618@OD2 Lig@O11 2.62 16.59
T404 19999-20031 Sentence denotes Asp618@OD2 Lig@O10 2.58 16.49
T405 20032-20287 Sentence denotes Asp618@OD1 Lig@O15 2.67 16.37 Finally, we supplemented the above results by analyzing the final conformation of each production simulation with the help of 2D LigPlot+ software, and different h-bonds and hydrophobic interactions were shown in Figure 7.
T406 20288-20410 Sentence denotes Hydrogen bonds are depicted in green dotted lines, while red semicircle residues are involved in hydrophobic interactions.
T407 20411-20576 Sentence denotes For the RdRp/remdesivir complex, Figure 7(A) displayed nine hydrophobic interactions with Lys545, Ala547, Ser549, Arg553, Val557, Asp684, Ser759, Ser814, and Arg836.
T408 20577-20690 Sentence denotes This large number of interactions account for the high stability and good binding affinity of remdesivir to RdRp.
T409 20691-20787 Sentence denotes EGCG formed hydrophobic interactions with Lys551, Ala554, Arg553, Arg624, Pro620, (Figure 7(B)).
T410 20788-20949 Sentence denotes In the case of TF3, eight hydrophobic interactions with His439, Ile548, Ser814, Phe812, Val557, Ser549, Tyr619 and Arg555 were formed as revealed by Figure 7(C).
T411 20950-21093 Sentence denotes Figure 7(D) shows that seven hydrophobic interactions with Asp833, His816, Pro832, Gln815, His872, His810 and Ser434 were formed for RdRp/TF2b.
T412 21094-21199 Sentence denotes Finally, Figure 7(E) shows that RdRp/TF2a formed hydrophobic interactions with Arg555, Ala554 and Lys551.
T413 21200-21366 Sentence denotes Overall, TF3 has a higher binding affinity toward RdRp compared to the other polyphenols due to a larger number of stable hydrogen bonds and hydrophobic interactions.
T414 21367-21376 Sentence denotes Figure 7.
T415 21378-21501 Sentence denotes The RdRp-ligands interaction profile for (A) RdRp/remdesivir, (B) RdRp/EGCG, (C) RdRp/TF3, (D) RdRp/TF2b and (E) RdRp/TF2a.
T416 21502-21563 Sentence denotes The polyphenols and remdesivir are shown in balls and sticks.
T417 21564-21685 Sentence denotes Hydrogen bonds are depicted in green dotted lines, and red semicircles residues are involved in hydrophobic interactions.
T418 21687-21691 Sentence denotes 3.3.
T419 21693-21788 Sentence denotes Prediction of the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile
T420 21789-22079 Sentence denotes In addition to testing the physiochemical efficiency of a given molecule to inhibit the target protein, other parameters such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the inhibitor play a critical role on demonstrating the likelihood of success of a drug.
T421 22080-22328 Sentence denotes Utilization of in-silico ADMET profiling, in combination with in vivo and in vitro predictions in the initial stage of the screening process, can significantly fasten the drug discovery process by minimizing the number of potential safety problems.
T422 22329-22572 Sentence denotes Hence, we performed a detailed ADMET profiling to evaluate the drug likeliness of the four polyphenols: EGCG, TF2a, TF2b, TF3 that exhibited the highest score from the MD simulation and MM-PBSA study along with the positive control remdesivir.
T423 22573-22736 Sentence denotes Human colon adenocarcinoma-2 cell line (Caco2) permeability and human intestinal absorption (HIA) are key parameters to decide the total bioavailability of a drug.
T424 22737-22943 Sentence denotes All the five compounds (EGCG, TF2a, TF2b, TF3, and remdesivir) showed comparatively low Caco2 permeability potential (<8 × 10−6 cm/s) and could be absorbed via the human intestine (Larregieu & Benet, 2013).
T425 22944-23097 Sentence denotes EGCG, TF2a, TF2b, TF3, and remdesivir were predicted to be substrates of permeability glycoprotein (P-glycoprotein), which is an efflux membrane protein.
T426 23098-23280 Sentence denotes However, remdesivir was predicted as a P-glycoprotein I inhibitor, and EGCG and TF3 as a P-glycoprotein II inhibitor, whereas TF2a and TF2b as both P-glycoprotein I and II inhibitor.
T427 23281-23428 Sentence denotes Hence, above mentioned five compounds could regulate the physiological functions of P-glycoprotein (see Table S3 in the Supplementary Information).
T428 23429-23602 Sentence denotes The distribution of a drug is regulated by many parameters such as lipid-solubility, concentration in plasma and binding ability to plasma proteins, transport proteins, etc.
T429 23603-23782 Sentence denotes The volume of distribution at steady-state (VDss) suggests that EGCG, TF2a, TF2b, TF3, and remdesivir had a lower theoretical dose required for uniform distribution in the plasma.
T430 23783-24015 Sentence denotes Further, the degree of diffusion across the plasma membrane increases in the following order remdesivir < EGCG < TF2a < TF2b < TF3 (Table S4 in the Supplementary Information) as measured by the fraction that is in the unbound state.
T431 24016-24246 Sentence denotes The predictions through the distribution of the drugs via the central nervous system and blood-brain barrier suggest that these five compounds are poorly distributed to the brain and unable to penetrate the central nervous system.
T432 24247-24383 Sentence denotes However, the medium level of the lipophilicity of the drugs suggests that they would have no negative impact on nervous system exposure.
T433 24384-24454 Sentence denotes Cytochromes P450 (CYP) isozymes play crucial roles in drug metabolism.
T434 24455-24585 Sentence denotes It has been observed that TF2a, TF3, and remdesivir are a substrate of CYP3A4 and hence, can be efficiently metabolized by CYP3A4.
T435 24586-24676 Sentence denotes On the other hand, EGCG is a CYP3A4 inhibitor (Table S5 in the Supplementary Information).
T436 24677-24859 Sentence denotes On a separate note, EGCG is predominantly metabolized in the small intestine and liver by the conjugate formation of glucuronide, methyl sulfates in the urine and plasma (Chow et al.
T437 24860-24866 Sentence denotes 2005).
T438 24867-25044 Sentence denotes Among the five compounds, TF2b and TF3 were predicted as the substrate of renal organic cation transporter-2 (Renal OCT2), as shown in Table S6 in the Supplementary Information.
T439 25045-25169 Sentence denotes While EGCG, TF2a, and remdesivir are possibly cleared through other available routes such as bile, breath, faces, and sweat.
T440 25170-25268 Sentence denotes EGCG remains intact in the plasma and later excreted via bile and metabolized by colon microflora.
T441 25269-25349 Sentence denotes It is also expected that all the compounds are absorbable via oral prescription.
T442 25350-25456 Sentence denotes We have also analyzed the toxicity profiles for EGCG, TF2a, TF2b, TF3 as well as remdesivir (see Table 7).
T443 25457-25625 Sentence denotes The toxicity prediction from the AMES test (Salmonella typhimurium reverse mutation assay) exhibited that all the compounds could be considered as non-mutagenic agents.
T444 25626-25701 Sentence denotes High toxicity was observed for all the compounds in Tetrahymena pyriformis.
T445 25702-25812 Sentence denotes EGCG, TF2a, TF2b, TF3, and remdesivir were shown to inhibit the human ether-a-go-go-related gene II (hERG II).
T446 25813-25955 Sentence denotes However, Remdesivir has been shown to induce hepatotoxicity, whilst EGCG, TF2a, TF2b, TF3 are not likely to be associated with hepatotoxicity.
T447 25956-26137 Sentence denotes The maximum recommended tolerated dose (MRTD) in human prediction shows that remdesivir violate MRTD whereas natural polyphenol EGCG, TF2a, TF2b, TF3 do not fall into this category.
T448 26138-26292 Sentence denotes Remdesivir does not possess high acute toxicity whereas EGCG, TF2a, TF2b, and TF3 regarded as high acute toxic compound as it falls under minnow toxicity.
T449 26293-26380 Sentence denotes Additionally, none of the compounds predicted to be associated with skin sensitization.
T450 26381-26389 Sentence denotes Table 7.
T451 26391-26459 Sentence denotes Predicted toxicity profile of EGCG, TF3, TF2b, TF2a, and remdesivir.
T452 26460-26462 Sentence denotes S.
T453 26463-26466 Sentence denotes No.
T454 26468-26506 Sentence denotes Compounds name Toxicity prediction  
T455 26507-26541 Sentence denotes     Properties Predicted values
T456 26542-26568 Sentence denotes 1 EGCG AMES toxicity No
T457 26569-26628 Sentence denotes     Maximum tolerated dose (Human) 0.441 (log mg/kg/day)
T458 26629-26655 Sentence denotes     hERG I inhibitor No
T459 26656-26684 Sentence denotes     hERG II inhibitor Yes
T460 26685-26737 Sentence denotes     Oral rat acute toxicity (LD50) 2.522 (mol/kg)
T461 26738-26803 Sentence denotes     Oral rat chronic toxicity (LOAEL) 3.065 (log mg/kg_bw/day)
T462 26804-26828 Sentence denotes     Hepatotoxicity No
T463 26829-26855 Sentence denotes     Skin sensitivity No
T464 26856-26898 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T465 26899-26934 Sentence denotes     Minnow toxicity 7.713 log mM
T466 26935-26960 Sentence denotes 2 TF3 AMES toxicity No
T467 26961-27020 Sentence denotes     Maximum tolerated dose (Human) 0.438 (log mg/kg/day)
T468 27021-27047 Sentence denotes     hERG I inhibitor No
T469 27048-27076 Sentence denotes     hERG II inhibitor Yes
T470 27077-27129 Sentence denotes     Oral rat acute toxicity (LD50) 2.482 (mol/kg)
T471 27130-27195 Sentence denotes     Oral rat chronic toxicity (LOAEL) 7.443 (log mg/kg_bw/day)
T472 27196-27220 Sentence denotes     Hepatotoxicity No
T473 27221-27247 Sentence denotes     Skin sensitivity No
T474 27248-27290 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T475 27291-27326 Sentence denotes     Minnow toxicity 9.738 log mM
T476 27327-27353 Sentence denotes 3 TF2b AMES toxicity No
T477 27354-27413 Sentence denotes     Maximum tolerated dose (Human) 0.438 (log mg/kg/day)
T478 27414-27440 Sentence denotes     hERG I inhibitor No
T479 27441-27469 Sentence denotes     hERG II inhibitor Yes
T480 27470-27522 Sentence denotes     Oral rat acute toxicity (LD50) 2.482 (mol/kg)
T481 27523-27588 Sentence denotes     Oral rat chronic toxicity (LOAEL) 5.322 (log mg/kg_bw/day)
T482 27589-27613 Sentence denotes     Hepatotoxicity No
T483 27614-27640 Sentence denotes     Skin sensitivity No
T484 27641-27683 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T485 27684-27719 Sentence denotes     Minnow toxicity 8.685 log mM
T486 27720-27746 Sentence denotes 4 TF2a AMES toxicity No
T487 27747-27806 Sentence denotes     Maximum tolerated dose (Human) 0.439 (log mg/kg/day)
T488 27807-27833 Sentence denotes     hERG I inhibitor No
T489 27834-27862 Sentence denotes     hERG II inhibitor Yes
T490 27863-27915 Sentence denotes     Oral rat acute toxicity (LD50) 2.484 (mol/kg)
T491 27916-27981 Sentence denotes     Oral rat chronic toxicity (LOAEL) 5.035 (log mg/kg_bw/day)
T492 27982-28006 Sentence denotes     Hepatotoxicity No
T493 28007-28033 Sentence denotes     Skin sensitivity No
T494 28034-28076 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T495 28077-28112 Sentence denotes     Minnow toxicity 4.898 log mM
T496 28113-28145 Sentence denotes 5 Remdesivir AMES toxicity No
T497 28146-28204 Sentence denotes     Maximum tolerated dose (Human) 0.15 (log mg/kg/day)
T498 28205-28231 Sentence denotes     hERG I inhibitor No
T499 28232-28260 Sentence denotes     hERG II inhibitor Yes
T500 28261-28313 Sentence denotes     Oral rat acute toxicity (LD50) 2.043 (mol/kg)
T501 28314-28379 Sentence denotes     Oral rat chronic toxicity (LOAEL) 1.639 (log mg/kg_bw/day)
T502 28380-28405 Sentence denotes     Hepatotoxicity Yes
T503 28406-28432 Sentence denotes     Skin sensitivity No
T504 28433-28475 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T505 28476-28511 Sentence denotes     Minnow toxicity 0.291 log mM
T506 28513-28517 Sentence denotes 3.4.
T507 28519-28602 Sentence denotes Identification of target class for natural polyphenol via target prediction studies
T508 28603-28808 Sentence denotes The polyphenolic structural motif of dietary polyphenols allows them to serve as excellent hydrogen bond donors which in turn help them to strongly interact with various biomacromolecules such as proteins.
T509 28809-28939 Sentence denotes This interaction is a critical step in the regulatory role of polyphenols on various key proteins involved in cellular physiology.
T510 28940-29085 Sentence denotes The majority, if not all, of the beneficial effect of polyphenols, can be explained via the functional consequence of proteins it interacts with.
T511 29086-29185 Sentence denotes Molecular target studies help us to predict therapeutic protein targets for a given small molecule.
T512 29186-29291 Sentence denotes Herein, we analyzed the predicted interacting proteins/enzymes for EGCG, TF2a, TF2b, TF3, and remdesivir.
T513 29292-29479 Sentence denotes This study is particularly important in the current context as we think that these polyphenols could target RdRp, an important enzyme that catalyzes the RNA replication in the SARS-CoV-2.
T514 29480-29659 Sentence denotes Notably, the molecular target analysis suggests that all four polyphenols possess excellent properties of druggability, and they interact with a diverse class of proteins/enzymes.
T515 29660-29782 Sentence denotes The top 25 target classes of EGCG, TF2a, TF2b, TF3, and remdesivir are represented in the pie-chart, as shown in Figure 8.
T516 29783-29977 Sentence denotes The detailed output table with the target, common name, UniProt ID, ChEMBL ID, target class, probability, and known actives in 2D/3D are listed in Tables S7–S11 in the Supplementary Information.
T517 29978-29987 Sentence denotes Figure 8.
T518 29989-30124 Sentence denotes Molecular target predictions for (A) EGCG, (B) TF2a, (C) TF2b (D) TF3, and (E) remdesivir obtained from swiss target prediction report.
T519 30125-30199 Sentence denotes The frequency of the target classes (top 25) is depicted in the pie chart.