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 rapidlyworldwide, causing a global pandemic. In the absence of a vaccine or a suitablechemotherapeutic intervention, it is an urgent need to develop a new antiviral drug to fight thisdeadly respiratory disease. In the present work, we have elucidated the mechanism of bindingof two inhibitors, namely α-ketoamide and Z31792168 to SARS-CoV-2 main protease (Mproor 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. Wecalculated the total binding free energy (ΔGbind) of both inhibitors and further decomposedΔGbind into various forces governing the complex formation using the MolecularMechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations revealthat α-ketoamide is more potent (ΔGbind= - 9.05 kcal/mol) compared to Z31792168 (ΔGbind= -3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative toZ31792168 arises due to an increase in the favorable electrostatic and van der Waalsinteractions between the inhibitor and 3CLpro. Further, we have identified important residuescontrolling the 3CLpro-ligand binding from per-residue based decomposition of the binding freeenergy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviraldrugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent comparedto both lopinavir and darunavir. In the case of lopinavir, a decrease in the size of the van derWaals interactions is responsible for the lower binding affinity compared to α-ketoamide. Onthe other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostaticand van der Waals interactions contributes to lower affinity compared to α-ketoamide. Ourstudy might help in designing rational anticoronaviral drugs targeting the SARS-CoV-2 mainprotease.