Binding and selectivity studies of phosphatidylinositol 3-kinase (PI3K) inhibitors

Overexpression of the Phosphatidylinositol 3-kinase (PI3K) proteins have been observed in cancer cells. Tar-geting the phosphatidylinositol 3-kinase (PI3K) signaling transduction pathway by inhibition of the PI3K sub-strate recognition sites has been proved to be an effective approach to block cancer progression. Many PI3K inhibitors have been developed. Seven drugs have been approved by the US FDA with a mechanism of targeting the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In this study, we used docking tools to investigate selective binding of ligands toward four different subtypes of PI3Ks (PI3K alpha, PI3K beta , PI3K gamma and PI3K delta). The affinity predicted from both the Glide dock and the Movable-Type (MT)-based free energy calculations agreed well with the experimental data. The validation of our predicted methods with a large dataset of 147 ligands showed very small mean errors. We identified residues that may dictate the subtype-specific binding. Particularly, residues Asp964, Ser806, Lys890 and Thr886 of PI3K gamma might be utilized for PI3K gamma-selective inhibitor design. Residues Val828, Trp760, Glu826 and Tyr813 may be important for PI3K delta-selective inhibitor binding.