3D-QSAR and molecular docking studies of 4-methyl quinazoline derivatives as PI3Kα inhibitors

A new series of 4- methyl quinazoline derivatives was synthesized and its anti-cancer activity was assessed. It was revealed that its compounds have potent inhibition on related phosphoinositide 3-kinases alpha (PI3Kα). In this study, the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking approaches were performed on a series of 4-methyl quinazoline derivatives with PI3Kα inhibitors. The 3D-QSAR study was applied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods, which gave the cross-validation coefficient (Q2) values of 0.850 and 0.92, the determination coefficient (R2) values of 0.998 and 0.987, and the standard error of the estimate (SEE) values of 0.017 and 0.105, respectively. The acceptable values of determination coefficient (R2 test) to CoMFA and CoMSIA respectively corresponding to values of 0.793 and 0.804 utilizing a test set of seven molecules prove the high predictive ability of this model. Using AutoDock tools, Molecular docking analysis was utilized to validate 3D-QSAR methods and to explain the binding site interactions and energy between the most active ligands and the PI3Kα (PDB ID: 4JPS) receptor. Based on these results, a novel series of 4- methyl quinazoline derivatives was predicted. [Display omitted] •4- Methyl Quinazoline derivatives as potent and selective PI3Kα inhibitors.•Construction of a reliable 3D-QSAR model of 4- Methyl Quinazoline derivatives.•Molecular docking as an efficient tool to calculate ligand–protein interactions.•Design of four new 4- Methyl Quinazoline derivatives as new PI3Kα inhibitors.