Computational Modeling of Novel Phosphoinositol‐3‐kinase γ Inhibitors Using Molecular Docking, Molecular Dynamics, and 3D‐QSAR

Phosphoinositol‐3‐kinase γ (PI3Kγ) is a member of the class‐IB PI3K superfamily and plays a significant role in G‐protein‐coupled receptor mediated cell signaling. Recent studies have suggested that elevated expression of PI3Kγ in tumor‐associated macrophages strongly influences immune suppression and tumor growth. Due to the presence of many isoforms of PI3K, the selective inhibition of PI3Kγ remains challenging. Therefore, it is necessary to design more potent inhibitors against PI3Kγ for cancer treatment. In this study, we have reported the critical interactions of isoindolinone‐based inhibitors with PI3Kγ by docking and molecular dynamics simulations. The binding free energy of the receptor‐ligand complex was calculated using molecular mechanics/Poison‐Boltzmann surface area approach. We have performed the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) to determine the structure–activity relationship of the inhibitors. The CoMFA ( q 2 = 0.681 and r 2 = 0.968) and CoMSIA ( q 2 = 0.665 and r 2 = 0.982) models showed reasonable predictive ability. Thereafter, the contour maps derived from CoMFA and CoMSIA were used to design several new compounds, among which, the compound D04 showed high predicted activity values. The designed compound was subjected to absorption‐distribution‐metabolism‐excretion/toxicity prediction and synthetic accessibility analyses. Our results could provide theoretical guidance for the future development of new PI3Kγ inhibitors.