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

[ Vol. 16 , Issue. 5 ]

Author(s):

Weineng Zhou, Shuai Lu, Yanmin Zhang, Lingfeng Yin, Lu Zhu, Junnan Zhao, Tao Lu, Yadong Chen* and Haichun Liu*   Pages 570 - 583 ( 14 )

Abstract:


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.

Keywords:

B-Raf kinase Type-II inhibitors, molecular docking, MM/PBSA, CoMFA, CoMSIA, binding site detection.

Affiliation:

School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, School of Basic Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198

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