Issue 41, 2021

Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding


The main protease (Mpro) of SARS-CoV-2 is central to viral maturation and is a promising drug target, but little is known about structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and an array of biomolecular simulation techniques, including automated docking, molecular dynamics (MD) and interactive MD in virtual reality, QM/MM, and linear-scaling DFT, to investigate the molecular features underlying recognition of the natural Mpro substrates. We extensively analysed the subsite interactions of modelled 11-residue cleavage site peptides, crystallographic ligands, and docked COVID Moonshot-designed covalent inhibitors. Our modelling studies reveal remarkable consistency in the hydrogen bonding patterns of the natural Mpro substrates, particularly on the N-terminal side of the scissile bond. They highlight the critical role of interactions beyond the immediate active site in recognition and catalysis, in particular plasticity at the S2 site. Building on our initial Mpro-substrate models, we used predictive saturation variation scanning (PreSaVS) to design peptides with improved affinity. Non-denaturing mass spectrometry and other biophysical analyses confirm these new and effective ‘peptibitors’ inhibit Mpro competitively. Our combined results provide new insights and highlight opportunities for the development of Mpro inhibitors as anti-COVID-19 drugs.

Graphical abstract: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding

Supplementary files

Article information

Article type
Edge Article
03 Jul 2021
05 Sep 2021
First published
06 Sep 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 13686-13703

Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding

H. T. H. Chan, M. A. Moesser, R. K. Walters, T. R. Malla, R. M. Twidale, T. John, H. M. Deeks, T. Johnston-Wood, V. Mikhailov, R. B. Sessions, W. Dawson, E. Salah, P. Lukacik, C. Strain-Damerell, C. D. Owen, T. Nakajima, K. Świderek, A. Lodola, V. Moliner, D. R. Glowacki, J. Spencer, M. A. Walsh, C. J. Schofield, L. Genovese, D. K. Shoemark, A. J. Mulholland, F. Duarte and G. M. Morris, Chem. Sci., 2021, 12, 13686 DOI: 10.1039/D1SC03628A

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