posted on 2021-08-17, 20:05authored byAnjela Manandhar, Vunnam Srinivasulu, Mohamad Hamad, Hamadeh Tarazi, Hany Omar, Dennis J. Colussi, John Gordon, Wayne Childers, Michael L. Klein, Taleb H. Al-Tel, Magid Abou-Gharbia, Khaled M. Elokely
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.