Computationally driven discovery of SARS-CoV-2 M^pro inhibitors: from design to experimental validation.

ABSTRACT: We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (M^pro) inhibitors whose potency ranges from mM for the initial non-covalent ligands to sub-μM for the final covalent compound (IC₅₀ = 830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energy calculations performed using the polarizable AMOEBA force field. The study is complemented by extensive adaptive sampling simulations that are used to rationalize the different ligand binding poses through the explicit reconstruction of the ligand-protein conformation space. Machine learning predictions are also performed to predict selected compound properties. While simulations extensively use high performance com

SUBMITTER: El Khoury L 

PROVIDER: S-EPMC8966641 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature