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

Abstract

AbstractThe main protease (Mpro) 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 Mpro activity (IC50=4.13±0.61 μM). However, how boceprevir inhibits Mpro 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 Mpro. The molecular docking analysis depicted a strong binding (−7.5 kcal/mol) of boceprevir to Mpro due to its hydrogen bond interactions with catalytic dyad (Cys145) and oxyanion hole residues (Asn142, Gly143) of Mpro. MD simulations revealed the structural stability of the Mpro‐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 Mpro, which is consistent with its high‐affinity binding with Mpro observed in the in vitro studies. The results from the current investigation will offer direction and valuable insights for developing novel Mpro inhibitors.