Primer for Designing Main Protease (Mpro) Inhibitors of SARS-CoV-2

Abhishek Thakur, Gaurav Sharma, Vishnu Nayak Badavath, Venkatesan Jayaprakash, Kenneth M. Merz, Galia Blum, Orlando Acevedo

Research output: Contribution to journalArticlepeer-review


The COVID-19 outbreak has been devastating, with hundreds of millions of infections and millions of deaths reported worldwide. In response, the application of structure-activity relationships (SAR) upon experimentally validated inhibitors of SARS-CoV-2 main protease (Mpro) may provide an avenue for the identification of new lead compounds active against COVID-19. Upon the basis of information gleaned from a combination of reported crystal structures and the docking of experimentally validated inhibitors, four "rules" for designing potent Mproinhibitors have been proposed. The aim here is to guide medicinal chemists toward the most probable hits and to provide guidance on repurposing available structures as Mproinhibitors. Experimental examination of our own previously reported inhibitors using the four "rules" identified a potential lead compound, the cathepsin inhibitor GB111-NH2, that was 2.3 times more potent than SARS-CoV-2 Mproinhibitor N3.

Original languageAmerican English
Pages (from-to)5776-5786
Number of pages11
JournalJournal of Physical Chemistry Letters
Issue number25
StatePublished - 30 Jun 2022

All Science Journal Classification (ASJC) codes

  • General Materials Science
  • Physical and Theoretical Chemistry


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