Targeting the Proangiogenic VEGF-VEGFR Protein-Protein Interface with Drug-like Compounds by In Silico and In Vitro Screening

Benoit Gautier, Maria A. Miteva, Victor Goncalves, Florent Huguenot, Pascale Coric, Serge Bouaziz, Bili Seijo, Jean-François Gaucher, Isabelle Broutin, Christiane Garbay, Aurelien Lesnard, Sylvain Rault, Nicolas Inguimbert, Bruno O. Villoutreix, Michel Vidal, Benoit Gautier, Maria A. Miteva, Victor Goncalves, Florent Huguenot, Pascale Coric, Serge Bouaziz, Bili Seijo, Jean-François Gaucher, Isabelle Broutin, Christiane Garbay, Aurelien Lesnard, Sylvain Rault, Nicolas Inguimbert, Bruno O. Villoutreix, Michel Vidal

Index: Chem. Biol. 18(12) , 1631-9, (2011)

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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 IC 50 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.