Integrated Molecular Modeling Techniques To Reveal Selective Mechanisms Of Inhibitors To Pi3k Delta With Marketed Idelalisib

Phosphatidylinositol-3-kinase (PI3K) is important for cell proliferation, differentiation, and apoptosis, and the diverse physiological roles of different PI3K isoforms have highlighted the significance of the development of PI3K delta inhibitors. A large number of PI3K delta inhibitors have been reported after the FDA approval of Idelalisib, but the clinical use of Idelalisib was limited because of its serious side effects. Therefore, great efforts have been made on the development of PI3K delta inhibitors with higher selectivity and lower toxicity, but there is no new PI3K delta inhibitor coming into the market so far. Even so, as the first listed PI3K inhibitor, Idelalisib could be used as an effective tool to investigate the selective inhibition mechanism of PI3K delta. Thus, in this study, a modeling strategy integrated 3D-QSAR, pharmacophore model, and molecular dynamics simulation was employed to reveal the key chemical characteristics of Idelalisib analogs and the binding pattern between the inhibitors and PI3K delta. First, the CoMFA model with high statistical significance was built to reveal the general structure-activity relationships. And then, a reliable pharmacophore model with a robust discrimination capability was constructed to expound the main chemical characteristics of the PI3K delta inhibitors. Finally, molecular dynamics simulation was conducted to explore the binding modes and some key residues refer to delta-selective binding were highlighted with binding-free energy calculation. In summary, these models and results would provide some effective help for the discovery or the rational design of novel PI3K delta inhibitors.