Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations

Background: The SARS-CoV-2 main protease (M-pro) is an attractive target in the COVID-19 drug development process. It catalyzes the polyprotein's translation from viral RNA and specifies a particular cleavage site. Due to the absence of identical cleavage specificity in human cell proteases, targeting M-pro with chemical compounds can obstruct the replication of the virus. Methods: To explore the potential binding mechanisms of 1,2,3-triazole scaffolds in comparison to co-crystallized inhibitors 11a and 11b towards M-pro, we herein utilized molecular dynamics and enhanced sampling simulation studies. Results and conclusion: All the 1,2,3-triazole scaffolds interacted with catalytic residues (Cys145 and His41) and binding pocket residues of M-pro involving Met165, Glu166, Ser144, Gln189, His163, and Met49. Furthermore, the adequate binding free energy and potential mean force of the topmost compound 3h was comparable to the experimental inhibitors 11a and 11b of M-pro. Overall, the current analysis could be beneficial in developing the SARS-CoV-2 M-pro potential inhibitors.

Automated summary

This study investigated the potential binding mechanisms of 1,2,3-triazole scaffolds with SARS-CoV-2 M-pro using molecular dynamics and enhanced sampling simulations. The results showed interactions between the scaffolds and key residues of M-pro, with comparable binding free energy to experimental inhibitors.