SARS-CoV-2 Main Protease Inhibitors: Structure-Based Enhancement to Anti-Viral Pre-Clinical GC376 Encourages Further Development.

SARS-CoV-2 Main protease (Mpro) is pivotal in viral replication and transcription. Mpro mediates proteolysis of translated products of replicase genes ORF1a and ORF1ab. Surveying pre-clinical trial Mpro inhibitors suggests potential enhanced efficacy for some moieties. Concordant with promising in vitro and in silico data, the protease inhibitor GC376 was chosen as a lead. Modification of GC376 analogues yielded a series of promising Mpro inhibitors. Design optimization identified compound G59i as lead candidate, displaying a binding energy of − 10.54 kcal/mol for the complex. Robust interactivity was noted between G59i and Mpro. With commendable ADMET characteristics and enhanced potency, further G59i analysis may be advantageous; moreover, identified key Mpro residues could contribute to the design of neotenic inhibitors. Serial modifications to the SARS-2-CoV main protease (Mpro) inhibitor GC376 yielded promising analogues from which compound G59i was progressed. A more exothermic binding energy was predicted for Mpro ligation compared to GC376. With commendable ADMET characteristics and enhanced potency, further G59i analysis may be advantageous. [ABSTRACT FROM AUTHOR]