Maria A. Miteva
University Paris Diderot, France
Title: In silico screening to discover inhibitors of protein-protein interactions targeting angiogenesis
Biography
Biography: Maria A. Miteva
Abstract
Targeting 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 protein-protein 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 protein-protein 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 structure-based 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 VEGF-induced VEGFR-1 transduction pathways. Our findings suggested that the new scaffolds can serve as a base for further development of new angiogenesis inhibitors
