Structure-based discovery of novel small molecule inhibitors of platelet-derived growth factor-B.

• Virtual screening was used for identifying two novel ligands antagonizing PDGF-B. • Inhibitory activity of the ligands was evaluated using in vitro bioassay. • Binding free energies were calculated for the ligand-protein complexes. • The results of in silico calculations were in agreement with in vitro bioassay. • The results can be used for design of novel anti-PDGF-B drugs. Platelet-derived growth factor (PDGF) is a family of growth factors with mitogenic and chemotactic activity. However, uncontrolled and overactivated PDGF signaling has been implicated in a variety of diseases, such as cancers and atherosclerosis. In this context, inhibition of PDGF-PDGFR signaling is of paramount importance in progression of such diseases. The purpose of the current study was to identify novel PDGF-B inhibitors using virtual screening methods. To this end, a combination of molecular modeling techniques such as molecular docking and dynamics simulation, as well as drug likeness filtering criteria, was applied to select anti-PDGF peptidomimetic candidates based on crystallography solved structure of an anti-PDGF-B monoclonal antibody named, MOR8457. In vitro biological assays of the selected compounds revealed two of them being active at micromolar IC 50 concentrations. The presented work can provide a framework for systematic peptidomimetic identification for anti-PDGF-B agents from large chemical libraries. [ABSTRACT FROM AUTHOR]