The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (Mpro)

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

Research output: Contribution to journalArticlepeer-review


With the potential for coronaviruses to re-emerge and trigger future pandemics, the urgent development of antiviral inhibitors against SARS-CoV-2 is essential. The Mpro enzyme is crucial for disease progression and the virus‘s life cycle. It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface. Among them, sites #2 and #5 possess druggable pockets and are predicted to bind drug-like molecules. Consequently, a commercially available ligand library containing ~7 million ligands was used to target site #2 via structure-based virtual screening. After extensive filtering, docking, and post-docking analyses, 53 compounds were chosen for biological testing. An oxindole derivative was identified as a Mpro non-competitive reversible inhibitor with a Ki of 115 μM and an IC50 of 101.9 μM. Throughout the 200 ns-long MD trajectories, our top hit has shown a very stable binding mode, forming several interactions with residues in sites #2 and #5. Moreover, derivatives of our top hit were acquired for biological testing to gain deeper insights into their structure-activity relationship. To sum up, drug-like allosteric inhibitors seem promising and can provide us with an additional weapon in our war against the recent pandemic, and possibly other coronaviruses-caused diseases.

Original languageEnglish (US)
Article numbere202301176
JournalChemistry and Biodiversity
Issue number11
StatePublished - Nov 2023


  • SARS-CoV-2
  • allosteric inhibitor
  • main protease
  • oxindole
  • virtual screening

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • General Chemistry
  • Molecular Medicine
  • Molecular Biology


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