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

SummaryProtein-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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (223 K)Download as PowerPoint slideHighlights► Protein-protein interactions are difficult to inhibit with small drug-like compounds ► The VEGF-VEGFR complex was selected because it has a very flat interface ► Small molecule inhibitors were found using in silico and in vitro screening ► Interaction of the best compound with the receptor was further investigated via NMR