Discovery of SARS-CoV-2 M^pro peptide inhibitors from modelling substrate and ligand binding.

ABSTRACT: The main protease (M^pro) 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 M^pro 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 t

SUBMITTER: Chan HTH 

PROVIDER: S-EPMC8549791 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature