Computational Identification of Possible Allosteric Sites and Modulators of the SARS-CoV‑2 Main Protease

In this study, we target the main
protease (Mpro) of
the SARS-CoV-2 virus as it is a crucial enzyme for viral replication.
Herein, we report three plausible allosteric sites on Mpro that can expand structure-based drug discovery efforts for new Mpro inhibitors. To find these sites, we used mixed-solvent
molecular dynamics (MixMD) simulations, an efficient computational
protocol that finds binding hotspots through mapping the surface of
unbound proteins with 5% cosolvents in water. We have used normal
mode analysis to support our claim of allosteric control for these
sites. Further, we have performed virtual screening against the sites
with 361 hits from Mpro screenings available through the
National Center for Advancing Translational Sciences (NCATS). We have
identified the NCATS inhibitors that bind to the remote sites better
than the active site of Mpro, and we propose these molecules
may be allosteric regulators of the system. After identifying our
sites, new X-ray crystal structures were released that show fragment
molecules in the sites we found, supporting the notion that these
sites are accurate and druggable.