From the calculated HOMO and LUMO energies, the energy gap of the compounds was calculated and observed that the energy gap of ECG (0.107783?eV) is slightly higher than the co-crystal ligand N3 (0.091682?eV) indicating similar reactive nature of ECG with N3. Table 3 Comparison of the values of orbital energy descriptors HOMO and LUMO thead th align=”left” rowspan=”1″ colspan=”1″ Molecule /th th align=”left” rowspan=”1″ colspan=”1″ HOMO energy (au) /th th align=”left” rowspan=”1″ colspan=”1″ LUMO energy (au) /th th align=”left” rowspan=”1″ colspan=”1″ Energy gap (eV) /th /thead N3???0.18692???0.0952380.091682ECG???0.19072???0.08293720.107783 Open in a separate window Since both N3 and ECG showed almost similar reactivity, therefore we further determined the IC50 value of ECG and N3 by performing QSAR analysis. (?)-epicatechin-3-O-gallate, which had shown the best binding affinity was subjected to molecular dynamics simulations to validate its binding affinity, during which, the root-mean-square-deviation values of SARS-CoV-2 MproCCo-crystal ligand (N3) and SARS-CoV-2 Mpro- (?)-epicatechin-3-O-gallate systems were found to be more stable than SARS-CoV-2 Mpro system. Further, (?)-epicatechin-3-O-gallate was subjected to QSAR analysis which predicted IC50 of 0.3281?nM against SARS-CoV-2 Mpro. Overall, (?)-epicatechin-3-O-gallate showed a potential binding affinity with SARS-CoV-2 Mpro and could be proposed as a potential natural compound for COVID-19 treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10211-9. Tensor Core graphic processor unit (GPU). For performing the MD Simulations, topology files of the small molecules N3 (co-crystal ligand) and (?)-epicatechin-3-O-gallate (ECG) were obtained from PRODRG [39, 40]. All defined systems were solvated with extended-SPC explicit solvent water model. Four Na+?ions were added to neutralize the system before energy minimization and position restraint MDs (NVT and NPT for 100?ps each). A water box of 5?? from the surface of the protein was created for all three systems. The systems were neutralized with counter-ions and energy minimization was performed using steepest descent for 50,000 steps. For all three systems (SARS-CoV-2 Mpro, SARS-CoV-2 Mpro-N3, and SARS-CoV-2 Mpro-ECG), the protein backbone was frozen and solvent molecules with counter-ions were allowed to move for two 100?ps position restrained equilibration MD runs. All simulations were performed under periodic boundary conditions with NVT followed by NPT ensemble. During the position restraint MD runs, V-rescale and Berendsen’s coupling algorithms were used to keep the temperature (310?K) and pressure (1?bar) constant, respectively. Finally, 100?ns of production MD runs were performed allowing all molecules to move in all directions according to a classical Newtonian leap-frog MD integrator. For all the systems, the pressure was maintained at 1?bar by isotropic pressure coupling in and components to a ParrinelloCRahman barostat with the time constant [Compound Name] and [PubChem CID][(?)-epicatechin-3-O-gallate (ECG)] [107905] ???46.2268 [(?)-epicatechin-3-O-gallate (ECG)] [107905] ???44.7288 [Phloretin] [4788] ???36.3649 [Nordihydroguaiaretic acid] [4534] ???35.3797 [Myrecetin] [5281672] ???35.091 [Propyl gallate] [4947] ???35.1536 [Epicatechin] [72276] ???33.3683 [Phloretin] [4788] ???33.0821 Open in a separate window To compare the binding of ECG with SARS-CoV-2 Mpro with the control, molecular docking was also performed between control molecules and the target proteins. Because ECG showed the highest binding affinity with SARS-CoV-2 Mpro, co-crystal ligands N3 and 13b were allowed to dock with SARS-CoV-2 Mpro. Between the controls, N3 (Supplementary Fig.?2) showed the lowest CDocker energy (??91.37?kcal?mol?1) after docking with SARS-CoV-2 Mpro. Surprisingly, the other control, that is, the ligand 13b showed CDocker energy???40.82?kcal?mol?1, which was lower than the CDocker energy of ECG. The co-crystal ligand of PLpro, i.e., Vir251 showed CDocker value???75.038?kcal?mol?1 with its target enzyme. Moreover, the numbers of H-bond formation between the ligand and receptor were analyzed and observed that both SARS-CoV-2 Mpro-N3 and SARS-CoV-2 Mpro-ECG complexes were created with six H-bonds. It is assumed that more numbers of H-bonds give a better tolerance to the mutability of the disease [2]. Because ECG showed the highest binding affinity with Mpro and created more numbers of H-bonds in comparison to all the test compounds, the complex of SARS-CoV-2 Mpro- ECG was taken for further studies, whereas, the complex SARS-CoV-2 Mpro-N3 was taken as control. Consequently, these two complexes were further analyzed by MM-PBSA binding energy calculation during 100?ns MD simulations to compute the binding behavior of the ligand to the receptor by mimicking in vitro and in vivo conditions [31, 50]. From your results from the MM-PBSA analysis, the average binding free energies (Vehicle der Waals contribution from MM, electrostatic energy as determined from the MM push field, solvation free energy comprising the energy contribution from solvent-accessible surface area (SASA), binding free energy Open in a separate windowpane Fig. 1 a (-)-Huperzine A Free energy of binding (of solvation of SARS-CoV-2 Mpro in SARS-CoV-2 MproCN3 and SARS-CoV-2 MproCECG systems were deduced and were displayed in Supplementary Fig.?4. Open in a separate windowpane Fig. 3 ProteinCligand connection analysis. a Short-range coulombic (black) and LennardCJones potentials (reddish) of inhibitor N3 interacting with.Molecular docking study using BIOVIA Discovery Studio 2018 revealed, (?)-epicatechin-3-O-gallate (ECG), a tea polyphenol has a binding affinity toward both the determined receptors, with the lowest CDocker energy???46.22?kcal?mol?1 for SARS-CoV-2 Mpro and CDocker energy???44.72?kcal?mol?1 for SARS-CoV-2 PLpro, respectively. 0.3281?nM against SARS-CoV-2 (-)-Huperzine A Mpro. Overall, (?)-epicatechin-3-O-gallate showed a potential binding affinity with SARS-CoV-2 Mpro and could be proposed like a potential natural compound for COVID-19 treatment. Supplementary Info The online version contains supplementary material available at 10.1007/s11030-021-10211-9. Tensor Core graphic processor unit (GPU). For carrying out the MD Simulations, topology documents of the small molecules N3 (co-crystal ligand) and (?)-epicatechin-3-O-gallate (ECG) were from PRODRG [39, 40]. All defined systems were solvated with extended-SPC explicit solvent water model. Four Na+?ions were added to neutralize the system before energy minimization and position restraint MDs (-)-Huperzine A (NVT and NPT for 100?ps each). A water package of 5?? from the surface of the protein was created for those three systems. The systems were neutralized with counter-ions and energy minimization was performed using steepest descent for 50,000 methods. For those three systems (SARS-CoV-2 Mpro, SARS-CoV-2 Mpro-N3, and SARS-CoV-2 Mpro-ECG), the protein backbone was freezing and solvent molecules with counter-ions were allowed to move for two 100?ps position restrained equilibration MD runs. All simulations were performed under periodic boundary conditions with NVT followed by NPT ensemble. During the position restraint MD runs, V-rescale and Berendsen’s coupling algorithms were used to keep the temp (310?K) and pressure (1?pub) constant, respectively. Finally, 100?ns of production MD runs were performed allowing all molecules to move in all directions according to a classical Newtonian leap-frog MD integrator. For all the systems, the pressure was managed at 1?pub by isotropic pressure coupling in and parts to a Esam ParrinelloCRahman barostat with the time constant [Compound Name] and [PubChem CID][(?)-epicatechin-3-O-gallate (ECG)] [107905] ???46.2268 [(?)-epicatechin-3-O-gallate (ECG)] [107905] ???44.7288 [Phloretin] [4788] ???36.3649 [Nordihydroguaiaretic acid] [4534] ???35.3797 [Myrecetin] [5281672] ???35.091 [Propyl gallate] [4947] ???35.1536 [Epicatechin] (-)-Huperzine A [72276] ???33.3683 [Phloretin] [4788] ???33.0821 Open in a separate window To compare the binding of ECG with SARS-CoV-2 Mpro with the control, molecular docking was also performed between control molecules and the prospective proteins. Because ECG showed the highest binding affinity with SARS-CoV-2 Mpro, co-crystal ligands N3 and 13b were allowed to dock with SARS-CoV-2 Mpro. Between the settings, N3 (Supplementary Fig.?2) showed the lowest CDocker energy (??91.37?kcal?mol?1) after docking with SARS-CoV-2 Mpro. Remarkably, the additional control, that is, the ligand 13b showed CDocker energy???40.82?kcal?mol?1, which was lower than the CDocker energy of ECG. The co-crystal ligand of PLpro, i.e., Vir251 showed CDocker value???75.038?kcal?mol?1 with its target enzyme. Moreover, the numbers of H-bond formation between the ligand and receptor were analyzed and observed that both SARS-CoV-2 Mpro-N3 and SARS-CoV-2 Mpro-ECG complexes were created with six H-bonds. It is assumed that more numbers of H-bonds give a better tolerance to the mutability of the disease [2]. Because ECG showed the highest binding affinity with Mpro and created more numbers of H-bonds in comparison to all the test compounds, the complex of SARS-CoV-2 Mpro- ECG was taken for further studies, whereas, the complex SARS-CoV-2 Mpro-N3 was taken as control. Consequently, these two complexes were further analyzed by MM-PBSA binding energy calculation during 100?ns MD simulations to compute the binding behavior of the ligand to the receptor by mimicking in vitro and in vivo conditions [31, 50]. From your results from the MM-PBSA analysis, the average binding free energies (Vehicle der Waals contribution from MM, electrostatic energy as determined from the MM push field, solvation free energy comprising the energy contribution from solvent-accessible surface area (SASA), binding free energy Open in a separate windowpane Fig. 1 a Free energy of binding (of solvation of SARS-CoV-2 Mpro in SARS-CoV-2 MproCN3 and SARS-CoV-2 MproCECG systems were deduced and were displayed in Supplementary Fig.?4. Open in a separate windowpane Fig. 3 ProteinCligand connection analysis. a Short-range coulombic (black) and LennardCJones potentials (reddish) of inhibitor N3.
