The Discovery of Small Allosteric and Active Site Inhibitors of the SARS-CoV-2 Main Protease via Structure-Based Virtual Screening and Biological Evaluation

Radwa E. Mahgoub, Feda E. Mohamed, Lara Alzyoud, Bassam R. Ali, Juliana Ferreira, Wael M. Rabeh, Shaikha S. AlNeyadi, Noor Atatreh, Mohammad A. Ghattas

Research output: Contribution to journalArticlepeer-review

Abstract

The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the Mpro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with Ki values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.

Original languageEnglish (US)
Article number6710
JournalMolecules
Volume27
Issue number19
DOIs
StatePublished - Oct 2022

Keywords

  • allosteric inhibitor
  • aryl nitrile
  • docking
  • M
  • SARS-CoV-2
  • structure-based virtual screening

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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