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

Perry, Elliot D.; Chapman, Simon and Xu, Yao-Zhong (2023). SARS-CoV-2 Main Protease Inhibitors: Structure-Based Enhancement to Anti-Viral Pre-Clinical GC376 Encourages Further Development. Journal of Computational Biophysics and Chemistry, 22(4) pp. 383–399.

DOI: https://doi.org/10.1142/s273741652350014x

Abstract

SARS-CoV-2 Main protease (M^pro) is pivotal in viral replication and transcription. M^pro mediates proteolysis of translated products of replicase genes ORF1a and ORF1ab. Surveying pre-clinical trial M^pro 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 M^pro 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 M^pro. With commendable ADMET characteristics and enhanced potency, further G59i analysis may be advantageous; moreover, identified key M^pro residues could contribute to the design of neotenic inhibitors.

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