3D-QSAR and molecular docking studies of aminopyrimidine derivatives as novel three-targeted Lck/Src/KDR inhibitors

Abstract In recent years, the development of multi-targeted inhibitors has captured extensive attention of research for treating of T-cell mediated autoimmune and inflammatory diseases. In this paper, three-dimensional quantitative structure-activity relationship and docking studies were performed on 41 aminopyrimidines as three-targeted Lck/Src/KDR inhibitors. The appropriate binding orientations and conformations of these compounds interacting with Lck, Src and KDR kinases were revealed by docking studies, and the established optimum CoMFA models yielded q 2  = 0.821, R 2  = 0.997 for Lck, q 2  = 0.803, R 2  = 0.998 for Src and q 2  = 0.819, R 2  = 0.997 for KDR, and the best CoMSIA models gave q 2  = 0.772, R 2  = 0.991 for Lck (SHD), q 2  = 0.866, R 2  = 0.997 for Src (SHD) and q 2  = 0.832, R 2  = 0.993 for KDR (SHA). Systemic external validations further confirm the satisfactory predictive power of these models, producing R 2 pred values of 0.836 and 0.821 for Lck, 0.837 and 0.843 for Src, and 0.828 and 0.848 for KDR, r 2 m values of 0.951 and 0.896 for Lck, 0.915 and 0.821 for Src, and 0.854 and 0.934 for KDR, respectively. Some structural factors influencing the activities of these compounds were discussed in detail. In addition, the key amino acids impacting the receptor-ligand interactions have been identified. The inhibitory activities of these compounds to inhibit isolated Lck, Src and KDR are well linearly correlated, demonstrating that similar interaction features may exist for this series of compounds. These theoretical results can offer useful references for designing novel potential three-targeted Lck/Src/KDR inhibitors.