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Computationally driven discovery of targeting SARS-CoV-2 Mpro inhibitors: from design to experimental validation

Abstract : We report a fast-track computationally-driven discovery of new SARS-CoV2 Main Protease (Mpro) inhibitors whose potency range from mM for 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 ligands binding poses through the explicit reconstruction of the ligand-protein conformation spaces. Machine Learning predictions are also performed to predict selected compound properties. While simulations extensively use High Performance Computing to strongly reduce time-to-solution, they were systematically coupled to Nuclear Magnetic Resonance experiments to drive synthesis and to in vitro characterization of compounds. Such study highlights the power of in silico strategies that rely on structure-based approaches for drug design and allows to address the protein conformational multiplicity problem. The proposed fluorinated tetrahydroquinolines open routes for further optimization of Mpro inhibitors towards low nM affinities.
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Contributor : Jean-Philip Piquemal Connect in order to contact the contributor
Submitted on : Friday, October 1, 2021 - 10:59:49 AM
Last modification on : Wednesday, September 28, 2022 - 5:53:27 AM


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Léa El Khoury, Zhifeng Jing, Daniele Loco, Alberto Cuzzolin, Alessandro Deplano, et al.. Computationally driven discovery of targeting SARS-CoV-2 Mpro inhibitors: from design to experimental validation. Chemical Science , The Royal Society of Chemistry, 2022, ⟨10.1039/D1SC05892D⟩. ⟨hal-03361062⟩



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