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

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 m...

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Autores principales: El Khoury, Léa, Jing, Zhifeng, Cuzzolin, Alberto, Deplano, Alessandro, Loco, Daniele, Sattarov, Boris, Hédin, Florent, Wendeborn, Sebastian, Ho, Chris, El Ahdab, Dina, Jaffrelot Inizan, Theo, Sturlese, Mattia, Sosic, Alice, Volpiana, Martina, Lugato, Angela, Barone, Marco, Gatto, Barbara, Macchia, Maria Ludovica, Bellanda, Massimo, Battistutta, Roberto, Salata, Cristiano, Kondratov, Ivan, Iminov, Rustam, Khairulin, Andrii, Mykhalonok, Yaroslav, Pochepko, Anton, Chashka-Ratushnyi, Volodymyr, Kos, Iaroslava, Moro, Stefano, Montes, Matthieu, Ren, Pengyu, Ponder, Jay W., Lagardère, Louis, Piquemal, Jean-Philip, Sabbadin, Davide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966641/
https://www.ncbi.nlm.nih.gov/pubmed/35432906
http://dx.doi.org/10.1039/d1sc05892d
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author El Khoury, Léa
Jing, Zhifeng
Cuzzolin, Alberto
Deplano, Alessandro
Loco, Daniele
Sattarov, Boris
Hédin, Florent
Wendeborn, Sebastian
Ho, Chris
El Ahdab, Dina
Jaffrelot Inizan, Theo
Sturlese, Mattia
Sosic, Alice
Volpiana, Martina
Lugato, Angela
Barone, Marco
Gatto, Barbara
Macchia, Maria Ludovica
Bellanda, Massimo
Battistutta, Roberto
Salata, Cristiano
Kondratov, Ivan
Iminov, Rustam
Khairulin, Andrii
Mykhalonok, Yaroslav
Pochepko, Anton
Chashka-Ratushnyi, Volodymyr
Kos, Iaroslava
Moro, Stefano
Montes, Matthieu
Ren, Pengyu
Ponder, Jay W.
Lagardère, Louis
Piquemal, Jean-Philip
Sabbadin, Davide
author_facet El Khoury, Léa
Jing, Zhifeng
Cuzzolin, Alberto
Deplano, Alessandro
Loco, Daniele
Sattarov, Boris
Hédin, Florent
Wendeborn, Sebastian
Ho, Chris
El Ahdab, Dina
Jaffrelot Inizan, Theo
Sturlese, Mattia
Sosic, Alice
Volpiana, Martina
Lugato, Angela
Barone, Marco
Gatto, Barbara
Macchia, Maria Ludovica
Bellanda, Massimo
Battistutta, Roberto
Salata, Cristiano
Kondratov, Ivan
Iminov, Rustam
Khairulin, Andrii
Mykhalonok, Yaroslav
Pochepko, Anton
Chashka-Ratushnyi, Volodymyr
Kos, Iaroslava
Moro, Stefano
Montes, Matthieu
Ren, Pengyu
Ponder, Jay W.
Lagardère, Louis
Piquemal, Jean-Philip
Sabbadin, Davide
author_sort El Khoury, Léa
collection PubMed
description 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.
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spelling pubmed-89666412022-04-14 Computationally driven discovery of SARS-CoV-2 M(pro) inhibitors: from design to experimental validation El Khoury, Léa Jing, Zhifeng Cuzzolin, Alberto Deplano, Alessandro Loco, Daniele Sattarov, Boris Hédin, Florent Wendeborn, Sebastian Ho, Chris El Ahdab, Dina Jaffrelot Inizan, Theo Sturlese, Mattia Sosic, Alice Volpiana, Martina Lugato, Angela Barone, Marco Gatto, Barbara Macchia, Maria Ludovica Bellanda, Massimo Battistutta, Roberto Salata, Cristiano Kondratov, Ivan Iminov, Rustam Khairulin, Andrii Mykhalonok, Yaroslav Pochepko, Anton Chashka-Ratushnyi, Volodymyr Kos, Iaroslava Moro, Stefano Montes, Matthieu Ren, Pengyu Ponder, Jay W. Lagardère, Louis Piquemal, Jean-Philip Sabbadin, Davide Chem Sci Chemistry 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. The Royal Society of Chemistry 2022-02-10 /pmc/articles/PMC8966641/ /pubmed/35432906 http://dx.doi.org/10.1039/d1sc05892d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
El Khoury, Léa
Jing, Zhifeng
Cuzzolin, Alberto
Deplano, Alessandro
Loco, Daniele
Sattarov, Boris
Hédin, Florent
Wendeborn, Sebastian
Ho, Chris
El Ahdab, Dina
Jaffrelot Inizan, Theo
Sturlese, Mattia
Sosic, Alice
Volpiana, Martina
Lugato, Angela
Barone, Marco
Gatto, Barbara
Macchia, Maria Ludovica
Bellanda, Massimo
Battistutta, Roberto
Salata, Cristiano
Kondratov, Ivan
Iminov, Rustam
Khairulin, Andrii
Mykhalonok, Yaroslav
Pochepko, Anton
Chashka-Ratushnyi, Volodymyr
Kos, Iaroslava
Moro, Stefano
Montes, Matthieu
Ren, Pengyu
Ponder, Jay W.
Lagardère, Louis
Piquemal, Jean-Philip
Sabbadin, Davide
Computationally driven discovery of SARS-CoV-2 M(pro) inhibitors: from design to experimental validation
title Computationally driven discovery of SARS-CoV-2 M(pro) inhibitors: from design to experimental validation
title_full Computationally driven discovery of SARS-CoV-2 M(pro) inhibitors: from design to experimental validation
title_fullStr Computationally driven discovery of SARS-CoV-2 M(pro) inhibitors: from design to experimental validation
title_full_unstemmed Computationally driven discovery of SARS-CoV-2 M(pro) inhibitors: from design to experimental validation
title_short Computationally driven discovery of SARS-CoV-2 M(pro) inhibitors: from design to experimental validation
title_sort computationally driven discovery of sars-cov-2 m(pro) inhibitors: from design to experimental validation
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966641/
https://www.ncbi.nlm.nih.gov/pubmed/35432906
http://dx.doi.org/10.1039/d1sc05892d
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