Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease

Chem Commun (Camb). 2021 Sep 9;57(72):9096-9099. doi: 10.1039/d1cc03953a.

Abstract

We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against the SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions P3 and P4 could be susceptible to improvement in order to get a larger binding strength. QM/MM simulations unveil the reaction mechanism for covalent inhibition, showing that the nitrile warhead facilitates the recruitment of a water molecule for the proton transfer step.

MeSH terms

  • Binding Sites
  • COVID-19 / pathology
  • COVID-19 / virology
  • Catalytic Domain
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / metabolism
  • Humans
  • Lactams / chemistry
  • Lactams / metabolism
  • Leucine / chemistry
  • Leucine / metabolism
  • Molecular Dynamics Simulation*
  • Nitriles / chemistry*
  • Nitriles / metabolism
  • Proline / chemistry
  • Proline / metabolism
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Quantum Theory
  • SARS-CoV-2 / enzymology*
  • SARS-CoV-2 / isolation & purification
  • Thermodynamics

Substances

  • Lactams
  • Nitriles
  • Protease Inhibitors
  • nirmatrelvir
  • Proline
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases
  • Leucine