Deciphering the potential of flavonols as SARS-CoV-2 M^Pro inhibitors: an in silico investigation using pass...

In the fight against contagious diseases, COrona VIrus disease 2019 (COVID -19) has been a formidable oponent. The SARS-CoV-2 virus, the etiological agent of COVID-19 continues to pose global health risks due to the ongoing mutations and post-COVID complications. Inhibiting the binding site of the SARS-CoV-2 Main Protease (M^Pro), with suitable inhibitors represents a promising therapeutic strategy to contain the pandemic. Flavonols, a class of flavonoid phytochemicals, exhibit a wide spectrum of biological activities. In this study, we assessed the inhibitory potential of 15 flavonols, using a multifaceted computational approach that included PASS prediction, molecular docking, Molecular Dynamics (MD) simulations and ADMET analysis. Our results identified Kaempferol as a potent M^Pro inhibitor, characterised by minimal RMSD, minimal RMSF and optimal Rg values. Furthermore, Kaempferol exhibited a superior safety profile and good oral bioavailability, outperforming the FDA-approved antiviral-Molnupiravir.

The online version contains supplementary material available at 10.1007/s40203-026-00574-y.