Elucidating Biophysical Basis of Binding of Inhibitors to SARS-CoV-2 Main Protease by Using Molecular Dynamics Simulations and Free Energy Calculations

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.