This research explores the molecular mechanism of action of three potential inhibitors—lopinavir, ritonavir, and nelfinavir—against the SARS-CoV-2 main protease (Mpro) using supervised molecular dynamics (SuMD). The study leverages the recently published crystallographic structure of Mpro to computationally investigate the binding pathways of these HIV protease inhibitors, which are being considered for COVID-19 treatment due to their promising in-vitro activity against related coronaviruses. SuMD simulations reveal detailed insights into the recognition processes, including key interactions and energy landscapes, for each inhibitor, providing a molecular-level understanding of their potential efficacy.

Giovanni Bolcato, Maicol Bissaro, Matteo Pavan, Mattia Sturlese, Stefano Moro