论文部分内容阅读
B-Raf has been identified as promising targets for novel anticancer agents. To further explore the interactions between small molecules and B-Raf, and to elucidate structural characteristics that influence the B-Raf kinase activity, molecular docking and three-dimensional quantitative structure-activity relationship(3D-QSAR) studies were performed on a dataset of 75 Type Ⅱ inhibitors. Molecular docking was applied to explore the detailed binding process between the inhibitors and B-Raf kinase in its DFG-out inactive conformation. Based on the conformations obtained by molecular docking strategy, 3D-QSAR models, including comparative molecular field analysis(CoMFA) and comparative molecular similarity indexes analysis(CoMSIA), were constructed. The established 3D-QSAR models show significant statistical quality and satisfactory predictive ability, with high q~2 and r~2 values: CoMFA model(q~2= 0.759, r~2 = 0.922), and CoMSIA model(q~2 = 0.685, r~2 = 0.945). The systemic external validation indicated that both CoMFA and CoMSIA models were quite robust and possess high predictive abilities with r~2 pred values of 0.633 and 0.708, respectively. Several key structural features accounting for the inhibitory activities of these compounds were discussed based on the 3D contour maps generated by the CoMFA and CoMSIA models, which were in good accordance with the docking results. These theoretical results rendered by 3D-QSAR models along with the docking may provide a useful reference for understanding the action mechanism and designing novel potential B-Raf inhibitors.
B further studies of promising molecules for B-Raf, and to elucidate structural characteristics that influence the B-Raf kinase activity, molecular docking and three-dimensional quantitative structure- Activity of the relationship (3D-QSAR) studies were performed on a dataset of 75 Type II inhibitors. Molecular docking was applied to explore the detailed binding process between the inhibitors and B-Raf kinase in its DFG-out inactive conformation. Based on the conformations obtained. by molecular docking strategy, 3D-QSAR models, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indicators analysis (CoMSIA), were constructed. The established 3D-QSAR models show significant statistical quality and satisfactory predictive ability, with high q ~ 2 and r ~ 2 values: CoMFA model (q ~ 2 = 0.759, r ~ 2 = 0.922) and CoMSIA model (q ~ 2 = 0.685, r ~ 2 = 0.945) Several key structural features accounting for the inhibitory activities of these compounds were discussed based on the 3D contour formed generated. by the CoMFA and CoMSIA models, which were in good accordance with the docking results. The theoretical results rendered by 3D-QSAR models along with the docking may provide a useful reference for understanding the action mechanism and designing novel potential B-Raf inhibitors.