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 (Early Access).

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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• Item ORO ID
• 87537
• Item Type
• Journal Item
• ISSN
• 2737-4173
• Keywords
• SARS-CoV-2; protease inhibition; computational chemistry; molecular modeling; molecular dynamics; SARS-CoV-2; Mpro; rational drug design; chemotherapeutics; antiviral drugs; RNAviruses
• Academic Unit or School
• Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
  Faculty of Science, Technology, Engineering and Mathematics (STEM)
• Copyright Holders
• © 2023 World Scientific Publishing Company
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