Structural Insights from Molecular Modeling of Isoindolin-1-One Derivatives as PI3Kγ Inhibitors against Gastric Carcinoma

The upregulation of phosphoinositol-3-kinase γ (PI3Kγ) is deemed to be positively correlated with tumor-associated-macrophage (TAM)-mediated gastric carcinoma (GC). PI3Kγ suppresses tumor necrosis factor-alpha (TNF-α) and interleukin-12 (IL-12) through activation of the AKT/mTOR pathway, which promotes the immunosuppressant phenotype of TAM. Unlike α and β isoforms, δ and γ isoforms are primarily distributed in leucocytes and macrophages. Dual inhibitors against PI3Kδ and PI3Kγ have been proven to have merits in targeting solid tumors. Furthermore, it has been found that PI3Kδ is activated by cytokines, while PI3Kγ is activated by G-protein-coupled receptors (GPCRs). This facilitates determining the functional difference between these two isoforms. For this goal, selective inhibitors would be immensely helpful. In the current manuscript, we conducted various molecular modeling studies with a series of isoindolin-1-one derivatives as potent PI3Kγ inhibitors by combining molecular docking, molecular dynamics (MD), molecular mechanics, Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA) binding free energy calculation, and three-dimensional structure–activity relationship (3D-QSAR) study. To evaluate the selectivity of γ isoform over δ, the molecular modeling studies of idelalisib analogs reported as PI3Kδ inhibitors were also investigated. The contour polyhedrons were generated from the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) around the ligand-bound active site for both isoforms, which could emphasize plausible explanations for the physicochemical factors that affect selective ligand recognition. The binding modalities of the two isoforms using CoMFA and MD models were compared, which suggested some key differences in the molecular interactions with the ligands and could be summarized as three subsites (one affinity subsite near the C-helix and DFG and two hydrophobic subsites). In the context of the structure–activity relationship (SAR), several new compounds were designed using a fragment-substitution strategy with the aim of selectively targeting PI3Kγ. The pIC(50) values of the designed compounds were predicted by the 3D-QSAR models, followed by the MM-PB/GBSA binding energy estimation. The overall findings suggest that the designed compounds have the potential to be used as PI3Kγ inhibitors with a higher binding affinity and selectivity.