Molecular modeling and simulations of some antiviral drugs, benzylisoquinoline alkaloid, and coumarin molecules to investigate the effects on Mpro main viral protease inhibition.

Background: SARS-CoV-2 is a deadly viral disease and uncounted deaths occurs since its first appearance in the year 2019. The antiviral drugs, benzylisoquinoline alkaloids, and coumarin molecules were searched using different online engines for drug repurposing with SARS-CoV-2 and to investigate the effects on main viral protease (Mpro) upon their bindings. Methods: A database composed of antiviral drugs, benzylisoquinoline alkaloids, and Coumarin molecules was screened through a molecular docking strategy to uncover the interactions of collected molecules with SARS-CoV-2 Mpro. Further, molecular dynamics simulations (MDS) were implemented for 100 ns to calculate the stability of the best complexed molecular scaffold with Mpro. The conformations of the simulated complexes were investigated by using principal component analysis (PCA) and Gibbs energy landscape (FEL) and DSSP together. Next, free binding energy (ΔGbind) was calculated using the mmpbsa method. Results: Molecular docking simulations demonstrate 17 molecules exhibited better binding affinity out of 99 molecules present in the database with the viral protease Mpro, followed ADMET properties and were documented. The Coumarin-EM04 molecular scaffold exhibited interactions with catalytical dyad HIS41, CYS145, and neighboring amino acids SER165 and GLN189 in the catalytical site. The crucial factor RMSD was calculated to determine the orientations of Coumarin-EM04. The Coumarin-EM04 complexed with Mpro was found stable in the binding site during MDS. Furthermore, the free energy binding ΔGbind of Coumarin-EM04 was found to be -187.471 ± 2.230 kJ/mol, and for Remdesivir ΔGbind was -171.926 ± 2.237 kJ/mol with SARS-CoV-2 Mpro. Conclusion: In this study, we identify potent molecules that exhibit interactions with catalytical dyad HIS41 and CYS145 amino acids and unravel Coumarin-EM04 exhibited ΔGbind higher than Remdesivir against Mpro and thus may serve better antiviral agent against SARS-CoV-2.