The recent outbreak of novel “coronavirus disease 2019” (COVID-19) has spread rapidly

worldwide, causing a global pandemic. In the absence of a vaccine or a suitable

chemotherapeutic intervention, it is an urgent need to develop a new antiviral drug to fight this

deadly respiratory disease. 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 (Mpro

or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We

calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed

ΔGbind 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 (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 to

Z31792168 arises due to an increase in the favorable electrostatic and van der Waals

interactions between the inhibitor and 3CLpro. Further, we have identified important residues

controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free

energy. Finally, we have compared ΔGbind 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 both lopinavir and darunavir. In the case of lopinavir, a decrease in the size of the 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 anticoronaviral drugs targeting the SARS-CoV-2 main

protease.

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