Computational investigation of the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib: combined molecular dynamics simulation and free energy calculation

Phosphoinositide 3-kinase (PI3K) has been considered to be a potential drug target for the treatment of several human body diseases. Nowadays, great efforts have been made on the development of selective PI3Kδ inhibitors because of the FDA approval of idelalisib, which is the first listed PI3K inhibitor. But serious side effects occur during the use of idelalisib that greatly promotes the development of novel PI3Kδ inhibitors. Nevertheless, idelalisib is still an important milestone in the development of selective PI3Kδ inhibitors, but the detailed selective binding mechanisms between idelalisib and PI3Ks have not been well elucidated. Therefore, in this study, an integrated modeling strategy combining molecular docking, molecular dynamics simulation, and free energy calculation was performed to reveal the molecular-level binding mechanisms of idelalisib and class I PI3K. First, molecular docking was carried on to obtain a reasonable binding posture of idelalisib in different PI3K isoforms. Then, key residues for selective inhibition of PI3Kδ were highlighted by molecular dynamics simulation and energy calculations. Finally, idelalisib was also compared with its lead compound, IC87114, to reveal the reason for the higher potency of Idelalisib for PI3Kδ. We hope that this study would provide some guidance for the rational design of selective PI3Kδ inhibitors. Graphical abstract