Insights into the Interaction Mechanism of Boceprevir with SARS-CoV-2 Main Protease

The main protease (M-pro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a prominent drug target as it plays a key role in viral replication and is greatly conserved in the coronaviruses with no homologues in the human genome. Ma et al. reported boceprevir, an FDA-approved hepatitis C virus (HCV) drug, for inhibiting SARS-CoV-2 M-pro activity (IC50=4.13 & PLUSMN;0.61 & mu;M). However, how boceprevir inhibits M-pro activity remains unexplored. The molecular dynamics (MD) simulations have been utilized in the present study to examine the mechanistic basis of the high-affinity binding of boceprevir with SARS-CoV-2 M-pro. The molecular docking analysis depicted a strong binding (-7.5 kcal/mol) of boceprevir to M-pro due to its hydrogen bond interactions with catalytic dyad (Cys145) and oxyanion hole residues (Asn142, Gly143) of M-pro. MD simulations revealed the structural stability of the M-pro-boceprevir complex during the whole simulation. The MD simulations illuminated key interactions of boceprevir with the residues lining the subpockets of the active site of M-pro, which is consistent with its high-affinity binding with M-pro observed in the in vitro studies. The results from the current investigation will offer direction and valuable insights for developing novel M-pro inhibitors.