Identification of potential platelet-derived growth factor receptor α inhibitors by computational screening and binding simulations.

Abstract

Platelet-derived growth factor receptor α (PDGFRα) is considered as a promising target for the treatment of fibrotic diseases. In this study, two types of pharmacophore model, which generated by ligand-based and receptor-based method, were put forward to identify novel chemical entities as PDGFRα inhibitors. It was found that some pharmacophore characteristics established by the two approaches overlap each other. In order to elucidate detailed interactions, representative molecules were selected to predict the conformations and binding modes of the molecules by molecular docking method. The calculation results of binding free energy illustrated that the van der Waals energy and nonpolar solvation were the most prominent contribution to the interactions between the inhibitors and PDGFRα. To further verify the accuracy of the docking results and the stability of the complexes system, the binding modes of two potent PDGFRα inhibitors were examined by 100\u2009ns molecular dynamics simulations. Herein, we reported the basic structural requirements of PDGFRα inhibitors for the first time through molecular docking and molecular dynamics simulations. Subsequently, the two pharmacophore models were used for virtual screening to query potential active molecules from Food and Drug Administration approved database. The hit molecules here might provide additional scaffolds for further optimization of PDGFRα inhibitors.