3D-QSAR and docking study on 3-benzimidazol-2-ylhydroquinolin-2-one derivatives as VEGFR-2 tyrosine kinase inhibitors

Abstract

The present study is an attempt to formulate the three-dimensional quantitative structure–activity relationship (3D-QSARs) modeling of 3-benzimidazol-2-ylhydroquinolin-2-one derivatives inhibiting vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase. The 3D-QSARs were established for 36 3-benzimidazol-2-ylhydroquinolin-2-one derivatives as VEGFR-2 tyrosine kinase inhibitors using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) techniques. The negative logarithm of IC50 (pIC50) was used as the biological activity in the 3D-QSAR study. With the CoMFA model, the cross-validated value (q2) was 0.516, the non-cross-validated value (R2) was 0.927, and the external cross-validated value (Qext2) was 0.855; with the CoMSIA model, the corresponding q2, R2, and Qext2 values were 0.538, 0.980, and 0.809, respectively. The CoMFA and CoMSIA models were validated by a structurally diversified test set of nine compounds. Then, molecular docking was carried out to better understand of the interactions between VEGFR-2 tyrosine kinase target and inhibitors. Finally, based on results of the structure–activity relationship and of the molecular docking, seven VEGFR-2 tyrosine kinase inhibitors that showed excellent potencies have been constructed.