Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations

Abstract

The recent outbreak of novel "coronavirus disease 2019" (COVID-19) has spread rapidly worldwide, causing a global pandemic. In the present work, we have elucidated the mechanism of binding of two inhibitors, namely a-ketoamide and Z31792168, to SARS-CoV-2 main protease (M pro or 3CL pro ) by using all-atom molecular dynamics simulations and free energy calculations. We calculated the total binding free energy (DG bind ) of both inhibitors and further decomposed DG bind into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that a-ketoamide is more potent (DG bind ¼ À 9.05 kcal/mol) compared to Z31792168 (DG bind ¼ À 3.25 kcal/mol) against COVID-19 3CL pro . The increase in DG bind for a-ketoamide relative to Z31792168 arises due to an increase in the favorable electrostatic and van der Waals interactions between the inhibitor and 3CL pro . Further, we have identified important residues controlling the 3CL pro -ligand binding from per-residue based decomposition of the binding free energy. Finally, we have compared DG bind of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that a-ketoamide is more potent compared to lopinavir and darunavir. In the case of lopinavir, a decrease in van der Waals interactions is responsible for the lower binding affinity compared to a-ketoamide. On the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic and van der Waals interactions contributes to lower affinity compared to a-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease.

Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

“…The LINCS algorithm was used for constraining all the bonds. Finally the systems were submitted to molecular dynamics simulation for 100 ns to observe stability of each EndoU-ligand complex Shukla et al, 2018;Sk et al, 2020).…”

In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials

“…Various strategies can be used to develop antiviral drugs, such as blocking viral binding to human cell receptors and inhibiting viral replication and self-assembly (Boopathi et al, 2020;Islam et al, 2020;Khan et al, 2020;Li et al, 2020;Sk et al, 2020;. Essential SARS-CoV-2 proteins 3CL pro and RdRp (nsp12) are prime targets due to their function in viral polyprotein processing and genome replication, respectively (Gorbalenya et al, 2006;Wu, Zhao, et al, 2020).…”

In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials

“…Various strategies can be used to develop antiviral drugs, such as blocking viral binding to human cell receptors and inhibiting viral replication and self-assembly (Boopathi et al, 2020;Islam et al, 2020;Khan et al, 2020;Li et al, 2020;Sk et al, 2020;Wu C and Zheng M, 2020). Essential SARS-CoV-2 proteins 3CL pro and RdRp (nsp12) are prime targets due to their function in viral polyprotein processing and genome replication, respectively (Gorbalenya et al, 2006;.…”