In Silico Design of New B-Raf Kinase Type-II Inhibitors Through Combined Molecular Modeling Studies

Background: B-Raf has become an important and exciting therapeutic cancer target. Methods: In the present work, molecular modeling protocols like molecular docking, MM/GBSA calculations, 3D-QSAR and binding site detection were performed on a dataset of 41 Type II inhibitors. Molecular docking was applied to explore the detailed binding process between the inhibitors and B-Raf kinase. Furthermore, the good linear relationships between G-Scores and MM/GBSA calculated and the experimental activity were shown. The satisfactory CoMFA and CoMSIA were constructed based on the conformations obtained by molecular docking. Results: The key structural requirements for increasing biological activity were verified by analyzing 3D contour maps of the 3D-QSAR models. FTMap and SiteMap were also used to detect the more efficient active binding site. Conclusion: New inhibitors were synthesized and the biological activities were evaluated, the results further validated our design strategy.