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-mM 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.

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

Cuzzolin, Alberto;Sturlese, M;Sosic, Alice;Barone, Marco;Gatto, Barbara;Macchia, Maria Ludovica.;Bellanda, M;Battistutta, Roberto;Salata, Cristiano;Moro, Stefano;
2022

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-mM 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.
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3415917
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact