基于分子对接和QSAR方法预测B-Raf II型抑制剂活性

引用本文: 刘海春, 卢帅, 冉挺, 张艳敏, 徐金星, 熊潇, 徐安阳, 陆涛, 陈亚东. 基于分子对接和QSAR方法预测B-Raf II型抑制剂活性[J]. 物理化学学报, 2015, 31(11): 2191-2206. doi: 10.3866/PKU.WHXB201510134 shu

Citation: 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 Physico-Chimica Sinica, 2015, 31(11): 2191-2206. doi: 10.3866/PKU.WHXB201510134 shu

基于分子对接和QSAR方法预测B-Raf II型抑制剂活性

刘海春 ^1, ,
卢帅 ^1, ,
冉挺 ^1, ,
张艳敏 ^1, ,
徐金星 ^1, ,
熊潇 ^1, ,
徐安阳 ^1, ,
陆涛 ^{1,2,
,} ,
陈亚东 ^{1,
,}

1.
1 中国药科大学理学院, 南京 211198;
2.
2 中国药科大学, 天然药物活性组分与药效国家重点实验室, 南京 210009

通讯作者: 陆涛, 陈亚东; 陆涛, 陈亚东

基金项目:
国家自然科学基金(21102181, 81302634)资助项目 (21102181, 81302634)

摘要: B-Raf激酶在促分裂素原活化蛋白激酶(MAPK)信号转导通路中起着重要作用, 已被确定为癌症治疗非常有吸引力的靶标. 新型高效B-Raf抑制剂的开发成为癌症治疗的一个热门研究领域. 本文以结构多样的B-Raf II型抑制剂为研究对象, 联合应用分子对接和定量构效关系(QSAR)模型研究其定量构效关系去探讨抑制活性的起源. 两个主题作为研究重点: 生物活性构象和描述符. 首先对分子对接方法(Glide、Gold、LigandFit、Cdocker和Libdock)进行准确性评价, 后将研究的对象分子对接到B-Raf活性位点并获得生物活性构象. 基于准确的对接结果, 计算得到16个打分评价函数和21个能量描述符, 以此构建定量构效关系模型. QSAR结果表明模型具有高度精确的拟合和强的预测能力(模型M1: r² = 0.852, r_(CV)² = 0.790, r_pre² = 0.864; 模型M2: r² = 0.738, r_(CV)² = 0.812, r_pre² = 0.8605). 同时探讨了对抑制活性有重要影响的描述符, 结果表明打分评价函数(G_Score, -ECD, Dock_Score, PMF)与能量描述符(S(hb_ext), DE(int), Emodel)对抑制活性影响非常大. 通过虚拟筛选和QSAR模型理论预测, 一些新的具有潜在抑制活性的化合物作为B-Raf II型抑制剂被获得. 上述信息对于进一步设计新颖高效的B-Raf II型抑制剂提供了有用的指导.

关键词:

English

Accurate Activity Predictions of B-Raf Type II Inhibitors via Molecular Docking and QSAR Methods

1.
1 School of Basic Science, China Pharmaceutical University, Nanjing 211198, P. R. China;
2.
2 State Key Laboratory of Natural Medcines, China Pharmaceutical University, Nanjing 210009, P. R. China

Corresponding author: 陆涛, 陈亚东; 陆涛, 陈亚东

Received Date: 09 July 2015
Fund Project:
国家自然科学基金(21102181, 81302634)资助项目

Abstract: 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, r_pre² = 0.864; M2: r² = 0.738, r_(CV)² = 0.812, r_pre² = 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.

Key words:

B-Raf Type II inhibitor
/ Molecular docking
/ Scoring function
/ Docking-generated energybased descriptor
/ Quantitative structure-activity relationship model

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基于分子对接和QSAR方法预测B-Raf II型抑制剂活性

通讯作者: 陆涛, 陈亚东; 陆涛, 陈亚东

English

Accurate Activity Predictions of B-Raf Type II Inhibitors via Molecular Docking and QSAR Methods

Corresponding author: 陆涛, 陈亚东; 陆涛, 陈亚东

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基于分子对接和QSAR方法预测B-Raf II型抑制剂活性

通讯作者: 陆涛, 陈亚东; 陆涛, 陈亚东

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Accurate Activity Predictions of B-Raf Type II Inhibitors via Molecular Docking and QSAR Methods

Corresponding author: 陆涛, 陈亚东; 陆涛, 陈亚东

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CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs