Article Dans Une Revue Chemical Science Année : 2022

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

Florent Hédin
Chris Ho
  • Fonction : Auteur
Theo Jaffrelot Inizan
  • Fonction : Auteur
  • PersonId : 1336006
  • IdHAL : tjaffrel2
Ivan Kondratov
  • Fonction : Auteur
Rustam Iminov
  • Fonction : Auteur
Andrii Khairulin
  • Fonction : Auteur
Anton Pochepko
  • Fonction : Auteur
Iaroslava Kos
  • Fonction : Auteur

Résumé

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 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.

Fichier principal
Vignette du fichier
d1sc05892d.pdf; (1.97 Mo) Télécharger le fichier
Origine Publication financée par une institution
Licence

Dates et versions

hal-03361062 , version 1 (10-02-2026)

Licence

Identifiants

Citer

Léa El Khoury, Zhifeng Jing, Alberto Cuzzolin, Alessandro Deplano, Daniele Loco, et al.. Computationally driven discovery of SARS-CoV-2 M pro inhibitors: from design to experimental validation. Chemical Science, 2022, 13 (13), ⟨10.1039/d1sc05892d⟩. ⟨hal-03361062⟩
577 Consultations
22 Téléchargements

Altmetric

Partager

  • More