Developing new PI3Kγ inhibitors by combining pharmacophore modeling, molecular dynamic simulation, molecular docking, fragment-based drug design, and virtual screening

Abstract

Since dysregulation of the phosphatidylinositol 3-kinase gamma (PI3Kγ) signaling pathway is associated with the pathogenesis of cancer, inflammation, and autoimmunity, PI3Kγ has emerged as an attractive target for drug development. IPI-549 is the only selective PI3Kγ inhibitor that has advanced to clinical trials, thus, IPI-549 could serve as a promising template for designing novel PI3Kγ inhibitors. In this present study, a modeling strategy consisting of common feature pharmacophore modeling, receptor-ligand pharmacophore modeling, and molecular dynamics simulation was utilized to identify the key pharmacodynamic characteristic elements of the target compound and the key residue information of the PI3Kγ interaction with the inhibitors. Then, 10 molecules were designed based on the structure-activity relationships, and some of them exhibited satisfactory predicted binding affinities to PI3Kγ. Finally, a hierarchical multistage virtual screening method, involving the developed common feature and receptor-ligand pharmacophore model and molecular docking, was constructed for screening the potential PI3Kγ inhibitors. Overall, we hope these findings would provide some guidance for the development of novel PI3Kγ inhibitors.