Binding of Inhibitors to the Monomeric and Dimeric SARS-CoV-2 Mpro

SARS-CoV-2 rapidly infects millions of people worldwide since December 2019. There is still no effective treatment for the virus, resulting in the death of more than one million of patients. Inhibiting the activity of SARS-CoV-2 main protease (Mpro), 3C-like protease (3CLP), is able to block the viral replication and proliferation. Although the dimer was shown to be the biologically active form of the SARS-CoV-2 Mpro, in this context, our study has revealed that in silico screening for inhibitors of SARS-CoV-2 Mpro can be reliably done using the monomeric structure of the receptor. Docking and fast pulling of ligand (FPL) simulations for both monomeric and dimeric forms correlate well with the corresponding experimental binding affinity data of 30 compounds. In particular, the correlation coefficients between computational and experimental binding free energy of the monomeric SARS-CoV-2 Mpro are approximately similar to the dimeric target. Moreover, the correlation coefficient between the rupture forces to binding free energy are roughly the same. Furthermore, the correlation coefficient between calculated metrics of the monomeric and dimeric SARS-CoV-2 Mpro is R = 0.74. Our study results show that it is possible to speed up computer-aided drug design for SARS-CoV-2 Mpro by focusing on the monomeric form instead of the larger dimeric one.