3D-QSAR and docking studies of 3-Pyridine heterocyclic derivatives as potent PI3K/mTOR inhibitors

摘要

Phosphoinosmde-3-kinase/ mammalian target of rapamycin (PI3K/mTOR) dual inhibitors have attracted a great deal of interest as antitumor drugs research. In order to design and optimize these dual inhibitors, two types of 3D-quantitative structure-activity relationship (3D-QSAR) studies based on the ligand alignment and receptor alignment were applied using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). In the study based on ligands alignment, models of PI3K (CoMFA with r~2, 0.770; q~2, 0.622; CoMSIA with r ~2, 0.945; q~2, 0.748) and mTOR (CoMFA with r~2, 0.850; q~2, 0.654; CoMSIA with r~2, 0.983; q~2, 0.676) have good predictability. And in the study based on receptor alignment, models of PI3K (CoMFA with r~2, 0.745; q~2, 0.538; CoMSIA with r~2, 0.938; q~2, 0.630) and mTOR (CoMFA with r ~2, 0.977; q~2, 0.825; CoMSIA with r~2, 0.985; q~2, 0.728) also have good predictability. 3D contour maps and docking results suggested different groups on the core parts of the compounds could enhance the biological activities. Finally, ten derivatives as potential candidates of PI3K/mTOR inhibitors with good predicted activities were designed.