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

Author(s): Weineng Zhou, Shuai Lu, Yanmin Zhang, Lingfeng Yin, Lu Zhu, Junnan Zhao, Tao Lu, Yadong Chen*, Haichun Liu*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 5 , 2019

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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.

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Article Details

VOLUME: 16
ISSUE: 5
Year: 2019
Page: [570 - 583]
Pages: 14
DOI: 10.2174/1570180815666180816121628
Price: $58

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