Discovery of 2-thiobenzimidazoles as noncovalent inhibitors of SARS-CoV-2 main protease

Bioorg Med Chem Lett. 2022 Sep 15:72:128867. doi: 10.1016/j.bmcl.2022.128867. Epub 2022 Jun 24.

Abstract

The discovery of antiviral agents against SARS-CoV-2 is an important step toward ending the COVID-19 pandemic and to tackle future outbreaks. In this context, the main protease (Mpro) represents an ideal target for developing coronavirus antivirals, being conserved among different strains and essential for survival. In this work, using in silico tools, we created and validated a docking protocol able to predict binders to the catalytic site of Mpro. The following structure-based virtual screening of a subset of the ZINC library (over 4.3 million unique structures), led to the identification of a hit compound having a 2-thiobenzimidazole scaffold. The inhibitory activity was confirmed using a FRET-based proteolytic assay against recombinant Mpro. Structure-activity relationships were obtained with the synthesis of a small library of analogs, guided by the analysis of the docking pose. Our efforts led to the identification of a micromolar Mpro inhibitor (IC50 = 14.9 µM) with an original scaffold possessing ideal drug-like properties (predicted using the QikProp function) and representing a promising lead for the development of a novel class of coronavirus antivirals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Benzimidazoles / pharmacology*
  • COVID-19 Drug Treatment*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / chemistry
  • Humans
  • Molecular Docking Simulation
  • Pandemics
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2*
  • Viral Nonstructural Proteins

Substances

  • Antiviral Agents
  • Benzimidazoles
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • 3C-like proteinase, SARS-CoV-2
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases