One microsecond MD simulations of the SARS-CoV-2 main protease and hydroxychloroquine complex reveal the intricate nature of binding

Currently, several vaccines and antivirals across the globe are in clinical trials. Hydroxychloroquine (HCQ) was reported to inhibit the SARS-CoV-2 virus in antiviral assays. Here, it raises the curiosity about the molecular target of HCQ inside the cell. It may inhibit some of the viral targets, or some other complex mechanisms must be at disposal towards action mechanisms. In some of the viruses, proteases are experimentally reported to be a potential target of HCQ. However, no in-depth investigations are available in the literature yet. Henceforth, we have carried out extensive, one-microsecond long molecular dynamics simulations of the bound complex of hydroxychloroquine with main protease (Mpro) of SARS-CoV-2. Our analysis found that HCQ binds within the catalytic pocket of Mpro and remains stable upto one-third of simulation time but further causes increased fluctuations in simulation parameters. In the end, the HCQ does not possess any pre-formed hydrogen bond, other noncovalent interactions with Mpro, ultimately showing the unsteadiness in binding at catalytic binding pocket and may suggest that HCQ may not inhibit the Mpro. In the future, this study would require experimental validation on enzyme assays against Mpro, and that may be the final say.

Automated summary

The study seeks to understand the molecular interactions between hydroxychloroquine and the main protease (Mpro) of SARS-CoV-2 through one-microsecond long molecular dynamics simulations. The analysis shows that hydroxychloroquine binds to the catalytic pocket of Mpro and remains stable for approximately one-third of the simulation time but causes increased fluctuations thereafter. The lack of pre-formed hydrogen bonds or other noncovalent interactions with Mpro suggests instability in binding at the catalytic pocket, indicating that hydroxychloroquine may not inhibit Mpro.