In silico screening to discover inhibitors of protein-protein interactions targeting angiogenesis

T protein-protein interactions by small organic molecules is an original approach to modulate protein targets involved in different pathologies. Structure-based virtual screening can be successfully used to discover hit/lead molecules binding proteinprotein interaction interfaces. We will briefly present in silico approaches allowing to efficiently modulate protein-protein interactions by small molecules, like considering protein flexibility or generating focused chemical compound libraries dedicated to inhibit proteinprotein interactions. We will present small-molecule inhibitors of protein-protein interactions targeting angiogenesis discovered by in silico screening. We will focus on neuropilin-1 (NRP-1) and the vascular endothelial growth factor receptor (VEGFR-1), two important co-receptors of vascular endothelial growth factor-A (VEGF-A), increasing thus its angiogenic action in several chronic diseases including cancer. After performing structural analysis of VEGF-A binding sites of the two receptors, we performed structurebased virtual screening and similarity search computations. We identified novel promising small drug-like molecules disrupting the binding of VEGF-A to NRP-1 and to the VEGFR-1 D2 domain in the low micro molar range. Potent compounds inhibited the VEGFinduced VEGFR-1 transduction pathways. Our findings suggested that the new scaffolds can serve as a base for further development of new angiogenesis inhibitors.