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

Benoit Gautier (1) , Maria A. Miteva (2) , Victor Goncalves (1) , Florent Huguenot , Pascale Coric , Serge Bouaziz , Bili Seijo (3) , Jean-François Gaucher , Isabelle Broutin (3) , Christiane Garbay (1) , Aurélien Lesnard (4) , Sylvain Rault (4) , Nicolas Inguimbert (1) , Bruno Villoutreix (1) , Michel Vidal (1)

1 PMC - UMR_S 648 - Pharmacochimie Moléculaire et Cellulaire
2 MTI - Molécules Thérapeutiques in silico
3 LCRB - UMR 8015 - Laboratoire de cristallographie et RMN biologiques
4 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie

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.

Domaines: Chimie thérapeutique

Benoit Gautier, Maria A. Miteva, Victor Goncalves, Florent Huguenot, Pascale Coric, et al.. Targeting the Proangiogenic VEGF-VEGFR Protein-Protein Interface with Drug-like Compounds by In Silico and In Vitro Screening. Chemistry and Biology, 2011, 18 (12), pp.1631-1639. ⟨10.1016/j.chembiol.2011.10.016⟩. ⟨hal-01061760⟩