3D-QSAR, molecular docking, and new compound design of pyrimidine derivatives as Src small molecule inhibitors

Abstract

Non-receptor tyromethod, The sine kinase Src is one of the important molecular targets for potential triple-negative breast cancer (TNBC). In this study, the structure and acitivity relationship of 51 Src small molecule inhibitors with potential pyrimidine derivatives was explored. On the basis of ligand composite, the relationsConducted a phase hip between molecular structure and inhibitory activity of MDA-MB-231/435 TNBC cell lines was studied by using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis fields (CoMSIA), and Topomer CoMFA (T-COMFA) methods, and thereby two sets of three-dimensional quantitative structure–activity relationship models were established to analyze the molecular structure and anti-TNBC activity. The results indicated that the q2 of CoMFA, CoMSIA, and Topomer CoMFA models was 0.698/0.719, 0.73/0.684, 0.674/0.683, and r2 was 0.994/0.991, 0.991/0.985, 0.946/0.959, respectively. Moreover, the three-dimensional equipotential map also revealed the relationship between structural characteristics and inhibitory activity, and molecular docking was investigated by Surflex-dock. The data proved that this model had good predictive ability and can further guide the design and modification of 3- (phenylethynyl) −1 hydropyrazolyl [3anilo-d] pyrimidine-4-amine derivatives inhibitors. According to the three-dimensional quantitative structure–activity relationship model of two TNBC cell lines of MDA-MB-231/435, 13 and 11 compounds were designed respectively, and the predicted activity values showed effective inhibition of SRC.