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ISSN 1000-6818CN 11-1892/O6CODEN WHXUEU
Acta Phys Chim Sin >> 2015,Vol.31>> Issue(11)>> 2191-2206     doi: 10.3866/PKU.WHXB201510134         中文摘要
BIOPHYSICAL CHEMISTRY
Accurate Activity Predictions of B-Raf Type II Inhibitors via Molecular Docking and QSAR Methods
LIU Hai-Chun1, LU Shuai1, RAN Ting1, ZHANG Yan-Min1, XU Jin-Xing1, XIONG Xiao1, XU An-Yang1, LU Tao1,2, CHEN Ya-Dong1
1 School of Basic Science, China Pharmaceutical University, Nanjing 211198, P. R. China;
2 State Key Laboratory of Natural Medcines, China Pharmaceutical University, Nanjing 210009, P. R. China
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B-Raf kinase plays an important role in the mitogen-activated protein kinase (MAPK) signaling transmission pathway and has been identified as an attractive target for cancer therapy. The exploitation of novel and efficient B-Raf inhibitors has become a hot research topic. In this study, we investigated quantitative structure-activity relationship (QSAR) to probe the origins of the inhibitory activities of B-Raf Type II inhibitors. We used structurally diverse B-Raf Type II inhibitors and an integrated docking and QSAR extended method. We focused mainly on two themes: bioactive conformations and descriptors. First, various molecular docking methods (Glide, Gold, LigandFit, Cdocker, and Libdock) were evaluated, and then all molecules were docked into the B-Raf active site to obtain the bioactive conformations. Secondly, based on the docking results, 16 scoring functions and 21 docking-generated energy-based descriptors were calculated to construct regression models. The results gave highly accurate fitting and had strong predictive abilities (M1: r2 = 0.852, r(CV)2 = 0.790, rpre2 = 0.864; M2: r2 = 0.738, r(CV)2 = 0.812, rpre2 = 0.8605). The important descriptors were also explored to elucidate the main factors influencing the inhibition activities. The models suggested that the scoring functions (G_Score, -ECD, Dock_Score, and PMF) and docking-generated energy-based descriptors (S(hb_ext), DE(int), and Emodel) were significant. Some new compounds that are potential B-Raf inhibitors were obtained through virtual screening and theoretical predictions using the established models. Such information is useful in guiding the design of novel and robust B-Raf Type II inhibitors.



Keywords: B-Raf Type II inhibitor   Molecular docking   Scoring function   Docking-generated energybased descriptor   Quantitative structure-activity relationship model  
Received: 2015-07-09 Accepted: 2015-10-12 Publication Date (Web): 2015-10-13
Corresponding Authors: LU Tao, CHEN Ya-Dong Email: lutao@cpu.edu.cn;ydchen@cpu.edu.cn

Fund: The project was supported by the National Natural Science Foundation of China (21102181, 81302634).

Cite this article: LIU Hai-Chun, LU Shuai, RAN Ting, ZHANG Yan-Min, XU Jin-Xing, XIONG Xiao, XU An-Yang, LU Tao, CHEN Ya-Dong. Accurate Activity Predictions of B-Raf Type II Inhibitors via Molecular Docking and QSAR Methods[J]. Acta Phys. -Chim. Sin., 2015,31 (11): 2191-2206.    doi: 10.3866/PKU.WHXB201510134

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