Primer for Designing Main Protease (M^pro) Inhibitors of SARS-CoV-2

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 (M^pro) 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 M^pro inhibitors 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 M^pro inhibitors. Experimental examination of our own previously reported inhibitors using the four "rules" identified a potential lead compound, the cathepsin inhibitor GB111-NH, that was 2.3 times more potent than SARS-CoV-2 M^pro inhibitor N3.