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

Davide Deodato, Nadeem Asad, Timothy M. Dore

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number128867
JournalBioorganic and Medicinal Chemistry Letters
StatePublished - Sep 15 2022

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


Dive into the research topics of 'Discovery of 2-thiobenzimidazoles as noncovalent inhibitors of SARS-CoV-2 main protease'. Together they form a unique fingerprint.

Cite this