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 (IC 50 =4.13±0.61 μM). 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.