PMC:7784834 / 17961-33874 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7784834","sourcedb":"PMC","sourceid":"7784834","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7784834","text":"3. Results and discussion\nSARS-CoV-2 is an enveloped non-segmented positively stranded RNA infectious virus that mainly affects enteric and respiratory systems (Graham et al., 2013). Its infection and amelioration in the host are majorly governed by several structural proteins (Joshi et al., 2020; Prajapat et al., 2020). 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). 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). 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 \u0026 Nitsche, 2020). The 3 D structures of spike protein and main protease were preprocessed, optimized and minimized to obtain the refined structures for drug repurposing.\n\n3.1. Binding pocket analysis\nThe binding pocket volume and surface area were determined through CASTp webserver. Binding pocket was forecasted at the surface as well as in the interior of proteins. Binding pocket volume of spike protein and main protease was 22,908 and 319 (SA), respectively which signifies an optimum space for ligand binding. 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. 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.\n\n3.2. Probable drugs against spike protein and main protease of SARS-CoV-2\nThe molecular docking studies were performed to determine the ligand interactions and their binding affinity with SARS-CoV-2 spike protein and main protease. The prepared ligands structures were docked against the binding sites of the target proteins. 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. The compounds displaying a HTVS glide score of more than −6.0 kJ/mol were employed for XP docking. 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. The docking analysis revealed a common compound, rutin (DrugBank ID: DB01698) which binds strongly to both the major targets of SARS-CoV-2. 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. 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. 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 \u0026 Ganeshpurkar, 2016). 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). To determine the interaction pattern between rutin and target proteins, their docked complexes were visualized using Ligplot (Figure 1). 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. The residues involved in the formation of hydrogen bonds between rutin and spike protein were F970, N969, H49, Q52, and T274. While the hydrophobic contact between the two involved residues T51, S50, S967 and S968. 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). 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. E166, T190, N142, H41 are found to be interacting with the inhibitor. In our study however, the inhibitor displayed slightly better binding efficiency than their report (Das et al., 2020). 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. 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.\nFigure 1. Protein-ligand interactions diagram of spike protein and main protease in complex with rutin. 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).\nTable 1. Intermolecular hydrogen bonds and hydrophobic residues showing close contact between spike protein with Rutin.\nSpike protein + rutin\nInteracting residue H-bond distance (Å) H-bond (D-H--A) Hydrophobic residues\nHis 49.A NE2–Rutin.het O15 3.28 HNE2-H--O15 Ser50, Thr51, Ser967, Ser968\nGLN 52.A OE1–Rutin.het O14 2.89 HOE1-H--O14  \nTHR 274.A OG1–Rutin.het O14 3.30 HOG1-H--O14  \nASN 969.A ND2–Rutin.het O10 3.17 HND2-H--O10  \nPHE 970.A N–Rutin.het O9 3.10 HN-H--O9  \nTable 2. Intermolecular hydrogen bonds and hydrophobic residues showing close contact between main protease with Rutin.\nMain protease + rutin\nInteracting residue H-bond distance (Å) H-bond (D-H--A) Hydrophobic residues\nTHR 26.A O–Rutin.het O15 3.05 HO-H--O15 Thr25, Leu27, His41, Met49, Gly143, His164,\nTHR 26.A O–Rutin.het O16 3.02 HO-H--O16 Met165, Leu167, Pro168, Arg188,\nTYR 54.A OH–Rutin.het O14 2.91 HOH-H--O14 Gln189\nASN 142.A OD1–Rutin.het O5 3.01 HOD1-H--O5  \nASN 142.A OD1–Rutin.het O7 2.91 HOD1-H--O7  \nGLU 166.A O–Rutin.het O8 3.02 HO-H--O8  \nASP 187.A O–Rutin.het O14 3.31 HO-H--O14  \nTHR 190.A O–Rutin.het O10 2.87 HO-H--O10  \n\n3.3. Molecular dynamics simulation of spike protein and main protease in absence and presence of rutin\nThe binding affinity of rutin against both spike and main protease were investigated through MD simulations using GROMACS. Separate MD simulations for spike protein and main protease with and without rutin for 100 ns were assessed through trajectory analysis. For the course of 100 ns MD simulation, the stable trajectory was observed and the representative structures were obtained. 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). 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. 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. 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. 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)). 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)). 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). 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.\nFigure 2. 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.\nFigure 3. 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. 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. Hence, we validated the residual fluctuations by calculating the mean fluctuation for stable trajectories of each simulation. 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. 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)). 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)). 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. 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.\nThe radius of gyration analysis was evaluated to determine the change in compactness of protein systems used throughout the MD simulations. 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)). 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. 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. 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)). 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.\nFurther, 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)). The most dominant cluster attained after 100 ns of MD simulation for all four systems are shown in Figure 4(E–H). Also, the secondary structure analyses of the stable trajectory for both the simulation systems were performed using the DSSP tool of GROMACS. 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). 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. 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.\nFigure 4. 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. 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.\nFigure 5. The secondary structure analysis of (A) spike protein, (B) spike-rutin complex, (C) main protease and (D) main protease-rutin complex. 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). 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)). 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). The average number of hydrogen bonds within spike-rutin and main protease-rutin are 3.72 and 2.29, respectively. 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. 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). Further, these results were strengthened by the vital contribution of the complex binding energies throughout the simulation run. 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.\nFigure 6. 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). The MD analysis plots representing hydrogen bonds with the potent inhibitor i.e. rutin against (C) main protease and (D) main protease-rutin complex.\nFigure 7. Superimposed structures of (A) spike protein before simulation (green) and after simulation (blue), and (B) main protease before simulation (yellow) and after simulation 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