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

Autor: El Khoury L; Qubit Pharmaceuticals, Incubateur Paris Biotech Santé 24 Rue du Faubourg Saint Jacques 75014 Paris France davide@qubit-pharmaceuticals.com., Jing Z; Qubit Pharmaceuticals, Incubateur Paris Biotech Santé 24 Rue du Faubourg Saint Jacques 75014 Paris France davide@qubit-pharmaceuticals.com., Cuzzolin A; Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche Largo Belloli 11a 43122 Parma Italy., Deplano A; Pharmacelera, Torre R, 4a planta Despatx A05, Parc Cientific de Barcelona, Baldiri Reixac 8 08028 Barcelona Spain., Loco D; Qubit Pharmaceuticals, Incubateur Paris Biotech Santé 24 Rue du Faubourg Saint Jacques 75014 Paris France davide@qubit-pharmaceuticals.com., Sattarov B; Qubit Pharmaceuticals, Incubateur Paris Biotech Santé 24 Rue du Faubourg Saint Jacques 75014 Paris France davide@qubit-pharmaceuticals.com., Hédin F; Qubit Pharmaceuticals, Incubateur Paris Biotech Santé 24 Rue du Faubourg Saint Jacques 75014 Paris France davide@qubit-pharmaceuticals.com., Wendeborn S; University of Applied Sciences and Arts Northwestern Switzerland, School of LifeSciences Hofackerstrasse 30 CH-4132 Muttenz Switzerland., Ho C; Qubit Pharmaceuticals, Incubateur Paris Biotech Santé 24 Rue du Faubourg Saint Jacques 75014 Paris France davide@qubit-pharmaceuticals.com., El Ahdab D; Sorbonne Université, Laboratoire de Chimie Théorique, UMR 7616 CNRS 75005 Paris France jean-philip.piquemal@sorbonne-universite.fr., Jaffrelot Inizan T; Sorbonne Université, Laboratoire de Chimie Théorique, UMR 7616 CNRS 75005 Paris France jean-philip.piquemal@sorbonne-universite.fr., Sturlese M; Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padua via F. Marzolo 5 35131 Padova Italy., Sosic A; Department of Pharmaceutical and Pharmacological Sciences, University of Padova via Marzolo 5 35131 Padova Italy., Volpiana M; Department of Pharmaceutical and Pharmacological Sciences, University of Padova via Marzolo 5 35131 Padova Italy., Lugato A; Department of Pharmaceutical and Pharmacological Sciences, University of Padova via Marzolo 5 35131 Padova Italy., Barone M; Department of Pharmaceutical and Pharmacological Sciences, University of Padova via Marzolo 5 35131 Padova Italy., Gatto B; Department of Pharmaceutical and Pharmacological Sciences, University of Padova via Marzolo 5 35131 Padova Italy., Macchia ML; Department of Pharmaceutical and Pharmacological Sciences, University of Padova via Marzolo 5 35131 Padova Italy., Bellanda M; Department of Chemistry, University of Padova via Marzolo 1 35131 Padova Italy., Battistutta R; Department of Chemistry, University of Padova via Marzolo 1 35131 Padova Italy., Salata C; Department of Molecular Medicine, University of Padua via Gabelli 63 35121 Padova Italy., Kondratov I; Enamine Ltd 78 Chervonotkats'ka Str. Kyiv 02094 Ukraine., Iminov R; Enamine Ltd 78 Chervonotkats'ka Str. Kyiv 02094 Ukraine., Khairulin A; Enamine Ltd 78 Chervonotkats'ka Str. Kyiv 02094 Ukraine., Mykhalonok Y; Enamine Ltd 78 Chervonotkats'ka Str. Kyiv 02094 Ukraine., Pochepko A; Enamine Ltd 78 Chervonotkats'ka Str. Kyiv 02094 Ukraine., Chashka-Ratushnyi V; Enamine Ltd 78 Chervonotkats'ka Str. Kyiv 02094 Ukraine., Kos I; Enamine Ltd 78 Chervonotkats'ka Str. Kyiv 02094 Ukraine., Moro S; Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padua via F. Marzolo 5 35131 Padova Italy., Montes M; Laboratoire GBCM, EA7528, Conservatoire National des Arts et Métiers, Hesam Université 2 Rue Conte 75003 Paris France., Ren P; University of Texas at Austin, Department of Biomedical Engineering TX 78712 USA., Ponder JW; Department of Chemistry, Washington University in Saint Louis MO 63130 USA.; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine MO 63110 USA., Lagardère L; Sorbonne Université, Laboratoire de Chimie Théorique, UMR 7616 CNRS 75005 Paris France jean-philip.piquemal@sorbonne-universite.fr., Piquemal JP; Sorbonne Université, Laboratoire de Chimie Théorique, UMR 7616 CNRS 75005 Paris France jean-philip.piquemal@sorbonne-universite.fr.; Institut Universitaire de France 75005 Paris France., Sabbadin D; Qubit Pharmaceuticals, Incubateur Paris Biotech Santé 24 Rue du Faubourg Saint Jacques 75014 Paris France davide@qubit-pharmaceuticals.com.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2022 Feb 10; Vol. 13 (13), pp. 3674-3687. Date of Electronic Publication: 2022 Feb 10 (Print Publication: 2022).
DOI: 10.1039/d1sc05892d
Abstrakt: 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 (IC 50 = 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 computing to strongly reduce the time-to-solution, they were systematically coupled to nuclear magnetic resonance experiments to drive synthesis and for in vitro characterization of compounds. Such a study highlights the power of in silico strategies that rely on structure-based approaches for drug design and allows the protein conformational multiplicity problem to be addressed. The proposed fluorinated tetrahydroquinolines open routes for further optimization of M pro inhibitors towards low nM affinities.
Competing Interests: P. R., M. M., L. L., J. W. P. and J.-P. P. are co-founders and shareholders of Qubit Pharmaceuticals.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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