Computational study reveals substituted benzimidazole derivatives’ binding selectivity to PI3Kδ and PI3Kγ

• Published in: Journal of molecular modeling 2022-05, Vol.28 (5), p.123-123, Article 123
• Main Authors: Zhang, Na-Na, Bai, Xue, Zhao, Shan-Shan, Zheng, Xue-Mei, Tang, Lei, Yang, Sheng-Gang, Zhang, Ji-Quan
• Format: Article
• Language: English
• Subjects: Apoptosis; Benzimidazoles - pharmacology; Binding sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Free energy; Homology; Kinases; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Medicine; Original Paper; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Residues; Selectivity; Theoretical and Computational Chemistry
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-022-05096-w

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors. Graphical abstract