LitCovid-sentences  

PMC:7784834 / 17961-33874 JSONTXT 2 Projects

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Id Subject Object Predicate Lexical cue
T119 0-2 Sentence denotes 3.
T120 4-26 Sentence denotes Results and discussion
T121 27-183 Sentence denotes SARS-CoV-2 is an enveloped non-segmented positively stranded RNA infectious virus that mainly affects enteric and respiratory systems (Graham et al., 2013).
T122 184-323 Sentence denotes Its infection and amelioration in the host are majorly governed by several structural proteins (Joshi et al., 2020; Prajapat et al., 2020).
T123 324-600 Sentence denotes Amidst numerous structural proteins, spike protein and main protease of SARS-CoV-2 are stated to show essential impacts on viral replication through proteolytic machinery and involvement in transcription, translation, and amplification of viral proteins (Paules et al., 2020).
T124 601-763 Sentence denotes Spike protein plays a critical role in binding to host cell receptor and is thought to represent a key determinant of the host range restriction (de Wilde, 2017).
T125 764-1040 Sentence denotes Main protease on the other hand exclusively cleaves polypeptide sequences after the glutamine residue and to the best of our knowledge is known as an ideal drug target due to the absence of human host cell protease showing this substrate specificity (Ullrich & Nitsche, 2020).
T126 1041-1192 Sentence denotes The 3 D structures of spike protein and main protease were preprocessed, optimized and minimized to obtain the refined structures for drug repurposing.
T127 1194-1198 Sentence denotes 3.1.
T128 1200-1223 Sentence denotes Binding pocket analysis
T129 1224-1307 Sentence denotes The binding pocket volume and surface area were determined through CASTp webserver.
T130 1308-1392 Sentence denotes Binding pocket was forecasted at the surface as well as in the interior of proteins.
T131 1393-1540 Sentence denotes Binding pocket volume of spike protein and main protease was 22,908 and 319 (SA), respectively which signifies an optimum space for ligand binding.
T132 1541-2045 Sentence denotes The binding residues as predicted in the binding cavity for spike protein were Y38-S45, V47-L54, P85-D88,T108,K195-Y200,K202-Y204,P225-D228,I233-R237,Q271-T274,C291-A292,E298,C301-K304,Y313-N317,R319-V327,D364-S366,Y369-N370,Y380-T393,P412,D427-T430,F515-H519,A522,P527-T531,N540-T549,Q564-D568,A570-T573,V576-R577,P579,I587,P589-F592,G594,M740-Y741,G744,F855-N856,Q954,Q957-A958,N960-D979,R983,V991,D994-R995,T998-R1000,Q1002-S1003,T1006-Y1007,Q1010, and R1014 around which the receptor grid was formed.
T133 2046-2214 Sentence denotes The receptor grid was also created around the catalytic region (T24-L27, H41, C44-S46, M49, P52, Y54, F140-C145, H163-P168, H172, D187-T190, and Q192) of main protease.
T134 2216-2220 Sentence denotes 3.2.
T135 2222-2290 Sentence denotes Probable drugs against spike protein and main protease of SARS-CoV-2
T136 2291-2448 Sentence denotes The molecular docking studies were performed to determine the ligand interactions and their binding affinity with SARS-CoV-2 spike protein and main protease.
T137 2449-2542 Sentence denotes The prepared ligands structures were docked against the binding sites of the target proteins.
T138 2543-2701 Sentence denotes The HTVS docking approach filtered out a large number of compounds on the basis of their binding interactions within the binding sites of the target proteins.
T139 2702-2800 Sentence denotes The compounds displaying a HTVS glide score of more than −6.0 kJ/mol were employed for XP docking.
T140 2801-2977 Sentence denotes The docking simulations evaluated a high Glide score for the compounds with best binding affinity and their interactions within the binding pocket of the binding site residues.
T141 2978-3117 Sentence denotes The docking analysis revealed a common compound, rutin (DrugBank ID: DB01698) which binds strongly to both the major targets of SARS-CoV-2.
T142 3118-3299 Sentence denotes Our study here presents rutin exhibiting high binding efficiency against spike protein and main protease with an XP Glide score of −8.367 kcal/mol and −11.553 kcal/mol respectively.
T143 3300-3481 Sentence denotes Rutin (3,3′,4′,5,7-pentahydroxyflavone-3-rhamnoglucoside) belongs to the flavonol class of compound, generously present in plants including buckwheat, apple, passion flower and tea.
T144 3482-3723 Sentence denotes It is well known to exhibit many bioactivities, such as anti-viral, anti-bacterial, ant-larvicidal, cytoprotective, anticarcinogenic, antioxidant, vasoprotective, cardioprotective and neuroprotective activities (Saluja & Ganeshpurkar, 2016).
T145 3724-3948 Sentence denotes The list of best ten candidates derived from the docking calculations with their corresponding docking score against spike protein and main protease are shown in supporting information (supporting material Tables S2 and S3).
T146 3949-4085 Sentence denotes To determine the interaction pattern between rutin and target proteins, their docked complexes were visualized using Ligplot (Figure 1).
T147 4086-4296 Sentence denotes The interaction pattern between rutin and spike protein revealed the formation of five hydrogen bonds and four hydrophobic interactions at the binding site, thereby contributing to the stability of the complex.
T148 4297-4422 Sentence denotes The residues involved in the formation of hydrogen bonds between rutin and spike protein were F970, N969, H49, Q52, and T274.
T149 4423-4511 Sentence denotes While the hydrophobic contact between the two involved residues T51, S50, S967 and S968.
T150 4512-4771 Sentence denotes The interactions between rutin and main protease was stabilized by residues E166, T190, Y54, D187, T26, N142 forming hydrogen bond and various hydrophobic contacts with residues P168, L167, H41, G143, T25, L27, M49, M165, H164, R188 and Q189 (Tables 1 and 2).
T151 4772-4948 Sentence denotes A similar study exploiting a blind molecular docking approach utilizing the Swiss Dock server also highlights main protease inhibition by rutin where by common amino acids viz.
T152 4949-5018 Sentence denotes E166, T190, N142, H41 are found to be interacting with the inhibitor.
T153 5019-5137 Sentence denotes In our study however, the inhibitor displayed slightly better binding efficiency than their report (Das et al., 2020).
T154 5138-5301 Sentence denotes From the contact analyses of both proteins, it can be attributed that rutin has high affinity and wide molecular contacts for both spike protein and main protease.
T155 5302-5501 Sentence denotes Also, it was further scrutinized by molecular dynamics simulations to attain insights towards the inhibitory aspects and efficacy to combat spike protein and main protease drug targets of SARS-CoV-2.
T156 5502-5511 Sentence denotes Figure 1.
T157 5513-5606 Sentence denotes Protein-ligand interactions diagram of spike protein and main protease in complex with rutin.
T158 5607-5808 Sentence denotes 2D Ligplot representation showing hydrogen bond and hydrophobic interactions, and 3D structure representation showing rutin in the binding pocket of spike protein (A and C) and main protease (B and D).
T159 5809-5817 Sentence denotes Table 1.
T160 5819-5929 Sentence denotes Intermolecular hydrogen bonds and hydrophobic residues showing close contact between spike protein with Rutin.
T161 5930-5951 Sentence denotes Spike protein + rutin
T162 5952-6031 Sentence denotes Interacting residue H-bond distance (Å) H-bond (D-H--A) Hydrophobic residues
T163 6032-6107 Sentence denotes His 49.A NE2–Rutin.het O15 3.28 HNE2-H--O15 Ser50, Thr51, Ser967, Ser968
T164 6108-6156 Sentence denotes GLN 52.A OE1–Rutin.het O14 2.89 HOE1-H--O14  
T165 6157-6206 Sentence denotes THR 274.A OG1–Rutin.het O14 3.30 HOG1-H--O14  
T166 6207-6256 Sentence denotes ASN 969.A ND2–Rutin.het O10 3.17 HND2-H--O10  
T167 6257-6300 Sentence denotes PHE 970.A N–Rutin.het O9 3.10 HN-H--O9  
T168 6301-6309 Sentence denotes Table 2.
T169 6311-6421 Sentence denotes Intermolecular hydrogen bonds and hydrophobic residues showing close contact between main protease with Rutin.
T170 6422-6443 Sentence denotes Main protease + rutin
T171 6444-6523 Sentence denotes Interacting residue H-bond distance (Å) H-bond (D-H--A) Hydrophobic residues
T172 6524-6610 Sentence denotes THR 26.A O–Rutin.het O15 3.05 HO-H--O15 Thr25, Leu27, His41, Met49, Gly143, His164,
T173 6611-6685 Sentence denotes THR 26.A O–Rutin.het O16 3.02 HO-H--O16 Met165, Leu167, Pro168, Arg188,
T174 6686-6737 Sentence denotes TYR 54.A OH–Rutin.het O14 2.91 HOH-H--O14 Gln189
T175 6738-6785 Sentence denotes ASN 142.A OD1–Rutin.het O5 3.01 HOD1-H--O5  
T176 6786-6833 Sentence denotes ASN 142.A OD1–Rutin.het O7 2.91 HOD1-H--O7  
T177 6834-6877 Sentence denotes GLU 166.A O–Rutin.het O8 3.02 HO-H--O8  
T178 6878-6923 Sentence denotes ASP 187.A O–Rutin.het O14 3.31 HO-H--O14  
T179 6924-6969 Sentence denotes THR 190.A O–Rutin.het O10 2.87 HO-H--O10  
T180 6971-6975 Sentence denotes 3.3.
T181 6977-7074 Sentence denotes Molecular dynamics simulation of spike protein and main protease in absence and presence of rutin
T182 7075-7197 Sentence denotes The binding affinity of rutin against both spike and main protease were investigated through MD simulations using GROMACS.
T183 7198-7334 Sentence denotes Separate MD simulations for spike protein and main protease with and without rutin for 100 ns were assessed through trajectory analysis.
T184 7335-7458 Sentence denotes For the course of 100 ns MD simulation, the stable trajectory was observed and the representative structures were obtained.
T185 7459-7694 Sentence denotes The deviation of the backbone atoms for simulated structures relative to the starting structures used as a reference was evaluated through RMSD for the backbone atoms (Figures 2 and 3) and C-alpha atoms (supporting material Figure S1).
T186 7695-7860 Sentence denotes A steep magnitude RMSD variation during the entire simulation can be an implication of a malleable and free instinctive protein or the alteration of the force field.
T187 7861-8104 Sentence denotes Depending upon the outcomes of the RMSD evaluation, Figure 2(A) represents that the RMSD fluctuation stabilize at about 50 ns MD simulations for both spike protein and spike protein in presence of rutin, and the simulation time was acceptable.
T188 8105-8258 Sentence denotes In the time from 50–100 ns, the RMSD for spike protein and spike-rutin complex have approximate values about 1.50–1.65 nm and 1.20–1.26 nm, respectively.
T189 8259-8430 Sentence denotes Similarly, the main protease in absence and presence of rutin for time from 20–70 ns and 20–100 ns showed RMSD values of about 0.25–0.30 nm and 0.20–0.25 nm (Figure 3(A)).
T190 8431-8594 Sentence denotes Interestingly, RMSD for both the complex systems were more stable than the native state of target receptor spike protein and main protease (Figures 2(A) and 3(A)).
T191 8595-8730 Sentence denotes The RMSD of C-alpha atoms were also attained and was found to be similar to the RMSD of backbone atoms (supporting material Figure S1).
T192 8731-8870 Sentence denotes The average RMSD for backbone and C-alpha atoms of both the protein and their complex with rutin are shown in supporting material Table S1.
T193 8871-8880 Sentence denotes Figure 2.
T194 8882-9175 Sentence denotes Representation of the MD analysis plots for spike protein (purple color) and spike-rutin complex (red color) (A) root mean square deviation (RMSD) for backbone atoms, (B) root mean square fluctuation (RMSF), (C) radius of gyration (Rg), and (D) solvent accessible surface area (SASA) analysis.
T195 9176-9185 Sentence denotes Figure 3.
T196 9187-9487 Sentence denotes Representation of the MD analysis plots for main protease (blue color) and main protease-rutin complex (green color) (A) root mean square deviation (RMSD) for backbone atoms, (B) root mean square fluctuation (RMSF), (C) radius of gyration (Rg) and (D) solvent accessible surface area (SASA) analysis.
T197 9488-9686 Sentence denotes The integral extent of the residual dynamic criterion is achieved by assessing the variations arising from shifts of each of the protein residues that majorly feature the most flexible chain frames.
T198 9687-9812 Sentence denotes Hence, we validated the residual fluctuations by calculating the mean fluctuation for stable trajectories of each simulation.
T199 9813-9968 Sentence denotes The RMSF evaluation of all the protein residues were achieved in order to check the residues that may have tend towards an enhancement in the RMSD results.
T200 9969-10211 Sentence denotes Compelling fluctuations existed in terminal residues and in various loops along β sheets and coils of the spike protein (residues 852-1000) to about 0.47 nm and spike-rutin (residues 62–90, 400–520 and 675–730) to about 0.65 nm (Figure 2(B)).
T201 10212-10531 Sentence denotes Similarly, in case of main protease and itself in complex with rutin showed fluctuations in the terminal residues and in some regions of β sheet with some coils and loops in main protease (residues 136-148) to about 0.37 nm and main protease-rutin (residues 39-52, 150-156) to about 0.37 nm, respectively (Figure 3(B)).
T202 10532-10767 Sentence denotes Also, we noticed that residues 270 to 350 in spike protein and 160 to 190 in main protease showed comparatively reduced discrepancy in RMSF values, which were the corresponding binding segment of both the complexes after MD simulation.
T203 10768-11050 Sentence denotes Interestingly, the binding region for spike-rutin and main protease-rutin before MD simulation were found to be the same after simulation, suggesting as a strong binding interaction of the rutin towards spike protein and main protease and indicating stability of both the complexes.
T204 11051-11190 Sentence denotes The radius of gyration analysis was evaluated to determine the change in compactness of protein systems used throughout the MD simulations.
T205 11191-11526 Sentence denotes The Rg plots for spike, main protease and its complex with rutin show slight fluctuations at the initial frame and attain compactness after 30 ns with Rg score of 3.85 nm and 4 nm (spike and spike-rutin) and after 20 ns with Rg score of 2.27 nm and 2.23 nm (main protease and main protease-rutin), respectively (Figures 2(C) and 3(C)).
T206 11527-11738 Sentence denotes When compared with spike protein, Rg value for spike-rutin is stabilized and remains constant, suggesting strong binding interaction of the inhibitor, and the same is observed in case of main protease and rutin.
T207 11739-11973 Sentence denotes Similar observations were determined through SASA analysis representing the solvent defined protein surface and its orientation through folding, making the alterations in the exposed and buried regions of the surface area of proteins.
T208 11974-12171 Sentence denotes The SASA values for all the simulation systems were about 460 nm/S2/N (spike), 485 nm/S2/N (spike-rutin), 154 nm/S2/N (main-protease), and 152 nm/S2/N (main protease-rutin) (Figures 2(D) and 3(D)).
T209 12172-12338 Sentence denotes Here, spike-rutin and main protease-rutin solvation profile shows a convincing SASA value suggesting a stable structure and strong binding interaction with the rutin.
T210 12339-12590 Sentence denotes Further, the cluster analysis with a RMSD based cut-off value of 0.25 nm demonstrated the development of 13,28,3 and 2 distinctive clusters for spike, spike-rutin, main protease, and main protease-rutin simulation systems respectively (Figure 4(A–D)).
T211 12591-12704 Sentence denotes The most dominant cluster attained after 100 ns of MD simulation for all four systems are shown in Figure 4(E–H).
T212 12705-12847 Sentence denotes Also, the secondary structure analyses of the stable trajectory for both the simulation systems were performed using the DSSP tool of GROMACS.
T213 12848-13094 Sentence denotes Both, spike and main protease were formed mainly of conserved β-sheet along with some connecting loops and α-helix with small coil regions as secondary structure elements infused with various small segments of bend, turn, and β-bridge (Figure 5).
T214 13095-13276 Sentence denotes Both cluster analysis and secondary structure analysis reveals the conformational changes before and after simulations for spike and main protease with and without rutin structures.
T215 13277-13467 Sentence denotes A noticeable observation through these analyses supports the rationale that spike protein and main protease binds with rutin firmly and attain similar interactions after MD simulations also.
T216 13468-13477 Sentence denotes Figure 4.
T217 13479-13686 Sentence denotes Representation of the MD analysis plots for the RMSD matrix cluster formation showing number of clusters in (A) spike protein, (B) spike-rutin complex, (C) main protease, and (D) main protease-rutin complex.
T218 13687-13853 Sentence denotes The most dominant cluster conformation after MD cluster analysis of (E) spike protein, (F) spike-rutin complex, (G) main protease and (H) main protease-rutin complex.
T219 13854-13863 Sentence denotes Figure 5.
T220 13865-13999 Sentence denotes The secondary structure analysis of (A) spike protein, (B) spike-rutin complex, (C) main protease and (D) main protease-rutin complex.
T221 14000-14223 Sentence denotes Further, hydrogen bond analysis revealed a higher number of hydrogen bonds with the surrounding water molecules in case of spike protein (2300 hydrogen bonds) than in complex with rutin (approximately, 2200 hydrogen bonds).
T222 14224-14377 Sentence denotes Similarly, in case of main protease, 700 hydrogen bonds were formed while 560 hydrogen bonds in case of main protease complex with rutin (Figure 6(A,B)).
T223 14378-14577 Sentence denotes In addition, the hydrogen bond landscape assessed against the inhibitor revealed the dynamic equilibration of the complex trajectories with a high number of hydrogen bonds, as shown in Figure 6(C,D).
T224 14578-14690 Sentence denotes The average number of hydrogen bonds within spike-rutin and main protease-rutin are 3.72 and 2.29, respectively.
T225 14691-14869 Sentence denotes The consistent numbers of hydrogen bonds were observed which contributed significantly to the proximal binding of the potent drug rutin with the spike and main protease receptor.
T226 14870-15015 Sentence denotes The superimposed structures of spike protein and main protease both in complex with rutin before and after simulations is shown in Figure 7(A,B).
T227 15016-15145 Sentence denotes Further, these results were strengthened by the vital contribution of the complex binding energies throughout the simulation run.
T228 15146-15324 Sentence denotes These calculations with consistent high binding energies and large hydrogen bonds involvement demonstrated the stable binding of rutin with both spike and main protease proteins.
T229 15325-15334 Sentence denotes Figure 6.
T230 15336-15574 Sentence denotes Representation of the MD analysis plots for the hydrogen bond with the surrounding solvent against (A) spike protein (purple color) and spike-rutin complex (red color), and (B) main protease (blue) and main protease-rutin complex (green).
T231 15575-15724 Sentence denotes The MD analysis plots representing hydrogen bonds with the potent inhibitor i.e. rutin against (C) main protease and (D) main protease-rutin complex.
T232 15725-15734 Sentence denotes Figure 7.
T233 15736-15913 Sentence denotes Superimposed structures of (A) spike protein before simulation (green) and after simulation (blue), and (B) main protease before simulation (yellow) and after simulation (pink).