Phosphoinositide 3‐kinase gamma (PI3Kγ) draws an increasing attention due to its link with deadly cancer, chronic inflammation and allergy. But the development of PI3Kγ selective inhibitors is still a challenging endeavor because of the high sequence homology with the other PI3K isoforms. In order to acquire valuable information about the interaction mechanism between potent inhibitors and PI3Kγ, a series of PI3Kγ isoform‐selective inhibitors were analyzed by a systematic computational method, combining 3D‐QSAR, molecular docking, molecular dynamic (MD) simulations, free energy calculations and decomposition. The general structure–activity relationships were revealed and some key residues relating to selectivity and high activity were highlighted. It provides precious guidance for rational virtual screening, modification and design of selective PI3Kγ inhibitors. Finally, ten novel inhibitors were optimized and P10 showed satisfactory predicted bioactivity, demonstrating the feasibility to develop potent PI3Kγ inhibitors through this computational modeling and optimization.

The phosphoinositide 3‐kinase γ (PI3Kγ) has been verified to be a potential drug target for the treatments of various human physical disorders. Although received lots of attention, the development of PI3Kγ‐selective inhibitors is still a challenging subject because of its unique protein structural features. Aiming to uncover the interaction mechanism between the selective inhibitors and PI3Kγ, a series of benzothiazole and thiazolopiperidine PI3Kγ isoform‐selective inhibitors were studied with an integrated in silico strategy by combining molecular docking, molecular dynamic simulations, binding free energy calculations, and decomposition analysis. Firstly, three molecular docking models, including rigid receptor docking, induced fit docking (IFD), and quantum mechanical‐polarized ligand docking, were respectively, built, and the IFD preliminarily predicted the docking poses of all studied inhibitors and roughly analyzed the binding mechanism. Secondly, four binding complexes with representative inhibitors were selected to perform molecular dynamic simulations and free energy calculations. The predicted binding energies were consistent with the experimental bioactivities and different binding patterns between potent and weak inhibitors were uncovered. Finally, through the Molecular Mechanics/Generalized Born Surface Area binding free energy decomposition, residue–inhibitor interactions spectra were obtained and several key residues contributing to favorable binding were highlighted, which provides valuable information for rational PI3Kγ inhibitor design and modification.