Exploring PI3Kγ binding preference with Eganelisib, Duvelisib, and Idelalisib via energetic, pharmacophore and dissociation pathway analyses.

Phosphatidylinositol 3-kinase (PI3K) is the central regulator of cellular functions and is suggested as a target for various diseases; thus, effective PI3K inhibitors provide a promising opportunity for the pharmaceutical intervention of many diseases. Among them, PI3Kγ has received more attention because of its essential role in immune signaling. However, the development of novel selective PI3Kγ inhibitors is a major challenge due to the high sequence homology across the class I PI3K isoforms. Therefore, understanding the substrate specificity and receptor-ligand interaction of PI3Kγ would be an appropriate strategy for the rational design of potent γ-selective inhibitors. In this study, by combining various molecular modeling approaches (including classic and enhanced sampling molecular dynamics (MD) simulations, end-point binding free energy calculations, and pharmacophore models), three quinolinone core-containing inhibitors, Idelalisib/CAL-101, Duvelisib/IPI-145, and Eganelisib/IPI-549, were employed to reveal the selective binding mechanisms targeting PI3Kγ. The classic MD and free energy calculations highlight the significant interaction and some key residues for the selective binding against PI3Kγ. Furthermore, the dissociation pathway analysis based on umbrella sampling simulations reveals that hydrophobic interactions are dominant for binding of the three ligands during the dissociation processes, and cooperation between the P-loop and the ligands always exists in the binding/dissociation process. Finally, the pharmacophore model revealed that IPI-549 contains a unique hydrophobic feature, and PI3Kγ exhibits an important hydrogen bond donor feature of hydrogen amide. These findings may provide some important information for the rational design and optimization of PI3Kγ-selective inhibitors.