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 α-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 (ΔG_bind) of both inhibitors and further decomposed ΔG_bind into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that α-ketoamide is more potent (ΔG_bind= - 9.05 kcal/mol) compared to Z31792168 (ΔG_bind= - 3.25 kcal/mol) against COVID-19 3CL^pro. The increase in ΔG_bind for α-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 ΔG_bind of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that α-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 α-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 α-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.