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The forced expression of phosphoinositide 3-kinase δ (PI3Kδ) in B cells was found to be oncogenic, rendering PI3Kδ an attractive drug target for chronic lymphocytic leukaemia. This study aimed to systemically explore the interaction mechanism of novel quinazolinone scaffold-based derivatives as PI3Kδ inhibitors using 3D-QSAR, molecular docking, pharmacophore model and molecular dynamics (MD) simulations. The 3D-QSAR models CoMFA, CoMSIA and Topomer CoMFA were established to discover critical structural factors affecting PI3Kδ inhibitory activity. The models showed suitable reliabilities (q2 0.741, 0.712 and 0.711) and predictive abilities (rpred2 0.851, 0.738 and 0.828, respectively). Contour maps indicated that the bioactivity of PI3Kδ inhibitor was affected most by electrostatic and hydrophobic fields. The Surflex-Dock and pharmacophore model result showed that enhancing the H-bond interaction of the key substituents around the 2- and 4-positions of pyrimidine with Glu826, Val828 and Asp911, as well as the electrostatic interactions of substituents around the 3-position of benzene with Ser831, Asp832 and Asn836, significantly affected the improvement in the activity and stability of the inhibitor. Based on these results, 10 novel PI3Kδ inhibitors with higher predicted activity and binding affinity were designed by introducing the heterocycles pyrrolopyridine or purine. 10 ns MD simulations further study the stable docking conformation of designed compounds, which showed strong hydrogen bond interactions with key residues Ser831 and Asp832 in a propeller-like fashion. These results provided strong guidance for the discovery and optimization of novel potent PI3Kδ selective inhibitors.

Molecular modeling studies of quinazolinone derivatives as novel PI3Kδ selective inhibitors