3D-QSAR and Molecular Docking Studies of Pyrimidine-based EGFR Inhibitors

Abstract: Epidermal growth factor tyrosine kinase receptor (EGFR) is expressed in a variety of tumors and has become a new target for anti-cancer drugs. In recent years, small molecule inhibitors targeting EGFR have been reported extensively. In this study, the structure–activity relationship of 119 pyrimidine EGFR inhibitors were studied based on comparative field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMISA). Performant models with high predictive ability were constructed (CoMFA model: q2 = 0.574, r 2 = 0.970, SEE = 0.163, F = 407.252; CoMSIA model: q2 = 0.575, r 2 = 0.968, SEE = 0.171, F = 286.102), according to which 9 new EGFR inhibitors were designed. MD simulation (100 ns) on the docked complex of compound N7 (the most active compound) shows that the small molecule binds with the protein stably. MM/PBSA calculation provided the binding free energy of the compound N7, -37.18 kcal·mol-1, lower than the original ligand. Newly designed molecules showed promising results in ADMET prediction. These results will provide valuable guidance for the design of novel EGFR inhibitors