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Targeting the proangiogenic VEGF-VEGFR protein-protein interface with drug-like compounds by in silico and in vitro screening
Authors:Gautier Benoit  Miteva Maria A  Goncalves Victor  Huguenot Florent  Coric Pascale  Bouaziz Serge  Seijo Bili  Gaucher Jean-François  Broutin Isabelle  Garbay Christiane  Lesnard Aurelien  Rault Sylvain  Inguimbert Nicolas  Villoutreix Bruno O  Vidal Michel
Institution:1Université Paris Descartes, CNRS UMR 8601, UFR biomédicale, 75006 Paris, France;2INSERM U973, Université Paris Diderot, 75013 Paris, France;3Université Paris Descartes, CNRS UMR 8638, UFR des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France;4Université Paris Descartes, CNRS UMR 8015, UFR des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France;5CERMN, Centre d'Etudes et de Recherche sur le Médicament de Normandie, 14032 Caen Cedex, France;6Université de Perpignan Via Domitia, laboratoire de chimie des biomolécules, 66860 Perpignan, France;7Laboratoire de Pharmacologie-Toxicologie, Service de Pharmacie, Hopital Cochin, 75014 Paris, France;8INSERM U648, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, 75006 Paris, France
Abstract:Protein-protein interactions play a central role in medicine, and their modulation with small organic compounds remains an enormous challenge. Because it has been noted that the macromolecular complexes modulated to date have a relatively pronounced binding cavity at the interface, we decided to perform screening experiments over the vascular endothelial growth factor receptor (VEGFR), a validated target for antiangiogenic treatments with a very flat interface. We focused the study on the VEGFR-1 D2 domain, and 20 active compounds were identified. These small compounds contained a (3-carboxy-2-ureido)thiophen unit and had IC50 values in the low micromolar range. The most potent compound inhibited the VEGF-induced VEGFR-1 transduction pathways. Our findings suggest that our best hit may be a promising scaffold to probe this macromolecular complex and for the development of treatments of VEGFR-1-dependent diseases.
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