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

Abstract : By using an ensemble-docking strategy, we undertook a large-scale virtual screeningcampaign in order to identify new putative hits against the MET kinase target. Following a largemolecular dynamics sampling of its conformational space, a set of 45 conformers of the kinasewas 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 theirpotential affinities towards the kinase binding site. The top 100 molecules selected—thanks to themolecular docking results—were further analyzed for their interactions, and 25 of the most promisingligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was themost efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with anIC50of 7.2μM. Interestingly, careful docking analysis of this molecule with MET suggests a possibleconformation halfway between classical type-I and type-II MET inhibitors, with an additional regionof interaction. This compound could therefore be an innovative seed to be repositioned from its initialantiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensembledocking strategy as a cost-effective functional method for drug development.
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https://hal.inria.fr/hal-03029061
Contributor : Bernard Maigret <>
Submitted on : Friday, November 27, 2020 - 7:46:37 PM
Last modification on : Wednesday, January 13, 2021 - 11:52:24 AM

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Emmanuel Bresso, Alessandro Furlan, Philippe Noel, Vincent Leroux, Flavio Maina, et al.. Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type. Molecules, MDPI, 2020, 25 (4), pp.938. ⟨10.3390/molecules25040938⟩. ⟨hal-03029061⟩

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