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Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type

Authors
  • Bresso, Emmanuel1
  • Furlan, Alessandro2, 3
  • Noel, Philippe1
  • Leroux, Vincent1
  • Maina, Flavio2
  • Dono, Rosanna2
  • Maigret, Bernard1
  • 1 Université de Lorraine, CNRS, Inria, LORIA, F-54000 Nancy, France
  • 2 Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), UMR7288, Parc Scientifique de Luminy, 13009 Marseille, France
  • 3 University of Lille, CNRS, UMR 8523, PhLAM-Physique des Lasers Atomes et Molécules, F-59000 Lille, France
Type
Published Article
Journal
Molecules
Publisher
MDPI AG
Publication Date
Feb 19, 2020
Volume
25
Issue
4
Identifiers
DOI: 10.3390/molecules25040938
PMID: 32093126
PMCID: PMC7070486
Source
PubMed Central
Keywords
License
Green

Abstract

By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC 50 of 7.2 μ M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway between classical type-I and type-II MET inhibitors, with an additional region of interaction. This compound could therefore be an innovative seed to be repositioned from its initial antiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensemble docking strategy as a cost-effective functional method for drug development.

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