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Manandhar A , Srinivasulu V , Hamad M , Tarazi H , Omar H , Colussi DJ , Gordon J , Childers W , Klein ML , Al-Tel TH , Abou-Gharbia M , Elokely KM
Discovery of Novel Small-Molecule Inhibitors of SARS-CoV-2 Main Protease as Potential Leads for COVID-19 Treatment
J Chem Inf Model. 2021 Aug 17;61(9) :4745-4757
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Abstract
The main protease of SARS-CoV-2 virus, M(pro), is an essential element for viral replication, and inhibitors targeting M(pro) 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 M(pro). These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC(50) 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 Cys(145) residue of M(pro). Our results highlight the challenges of targeting M(pro) protease and pave the way toward the discovery of potent lead molecules.
Notes
1549-960x Manandhar, Anjela Srinivasulu, Vunnam Hamad, Mohamad Tarazi, Hamadeh Omar, Hany Orcid: 0000-0002-4670-8149 Colussi, Dennis J Gordon, John Childers, Wayne Klein, Michael L Orcid: 0000-0002-0027-9262 Al-Tel, Taleb H Orcid: 0000-0003-4914-9677 Abou-Gharbia, Magid Orcid: 0000-0001-7524-6011 Elokely, Khaled M Orcid: 0000-0002-2394-021x Journal Article United States J Chem Inf Model. 2021 Aug 17. doi: 10.1021/acs.jcim.1c00684.