Action mechanisms and structure-activity relationships of PI3Kγ inhibitors on the enzyme: a molecular modeling study

Action mechanisms of four types of PI3Kγ inhibitors were investigated on the ligand-binding pocket (LBP) of PI3Kγ with molecular modeling method. At first five compounds whose complex structures with PI3Kγ were available experimentally were used to validate the reliability of docking program Autodock3.0. The results demonstrated that the program could reproduce the bound conformations of those compounds in crystal structures. Then the program was used to dock all the four types of PI3Kγ inhibitors into the LBP of the enzyme. The predicted activities of these compounds were in agreement with their experimental activities, and a pharmacophore model was hence derived for these compounds, which consisted of one hydrophobic portion flanked by two symmetric hydrophilic portions. Furthermore, the structure-activity relationships of PI3Kγ inhibitors were elucidated and the activity differences between them were discussed.