2. Academic Validation
  3. Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment

Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment

  • J Chem Inf Model. 2021 Sep 27;61(9):4745-4757. doi: 10.1021/acs.jcim.1c00684.
Anjela Manandhar 1,  Vunnam Srinivasulu 2,  Mohamad Hamad 2,  Hamadeh Tarazi 3,  Hany Omar 2 3,  Dennis J Colussi 4,  John Gordon 4,  Wayne Childers 4,  Michael L Klein 1,  Taleb H Al-Tel 2 3,  Magid Abou-Gharbia 4,  Khaled M Elokely 1 5
Affiliations

Affiliations

  • 1 Institute for Computational Molecular Science, and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.
  • 2 Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 3 College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 4 Moulder Center for Drug Discovery Research, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, Pennsylvania 19122, United States.
  • 5 Department of Pharmaceutical Chemistry, Tanta University, Tanta 31527, Egypt.
PMID: 34403259 DOI: 10.1021/acs.jcim.1c00684
Abstract

The main protease of SARS-CoV-2 virus, Mpro, is an essential element for viral replication, and inhibitors targeting Mpro are currently being investigated in many drug development programs as a possible treatment for COVID-19. An in vitro pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for Mpro. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC50 value of 20.7 μM. Molecular modeling studies were performed to understand the binding characteristics of the identified compounds. The presence of a cyclohexenone warhead group facilitated covalent binding with the Cys145 residue of Mpro. Our results highlight the challenges of targeting Mpro protease and pave the way toward the discovery of potent lead molecules.

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