高等学校化学学报

高等学校化学学报

• 研究论文 • 上一篇    下一篇

Combretastatins类微管蛋白抑制剂的定量构效关系与结合模式

田然1,2, 季宇彬1, 刘振明2, 金宏威2, 张亮仁2, 林文翰1,2   

    1. 哈尔滨商业大学生命科学与环境科学研究中心, 哈尔滨 150076;
    2. 北京大学药学院, 天然药物及仿生药物国家重点实验室, 北京 100083
  • 收稿日期:2007-03-06 修回日期:1900-01-01 出版日期:2007-11-10 发布日期:2007-11-10
  • 通讯作者: 张亮仁

QSAR and Binding Mode of a Series of Combretastatin Analogues as Tubulin Inhibitors

TIAN Ran1,2, JI Yu-Bin1, LIU Zhen-Ming2, JIN Hong-Wei2, ZHANG Liang-Ren2*, LIN Wen-Han1,2*   

    1. Research Center on Life Science and Environmental Science, Harbin University of Commerce, Harbin 150076, China;
    2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China
  • Received:2007-03-06 Revised:1900-01-01 Online:2007-11-10 Published:2007-11-10
  • Contact: ZHANG Liang-Ren

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被引次数

6

摘要： 以Combretastatins的B环改造化合物为研究对象, 采用遗传函数分析方法进行了二维定量构效关系研究. 研究结果表明, Apol, PMI-mag, Dipole-mag, Hbond donor和RadOfGyration等描述符对该系列抑制剂活性的贡献最大. 采用比较分子场分析方法(CoMFA)和比较分子相似因子分析方法(CoMSIA)进行了三维定量构效关系研究, 建立的CoMFA和CoMSIA模型的交叉验证相关系数q2分别为0.630和0.634, 具有较强的预测能力. 利用CoMFA和CoMSIA模型的三维等势图解析了Combretastatins类化合物的构效关系, 阐明了B环上各取代基对抑制微管蛋白聚合活性的影响, 同时应用分子对接方法分析并验证了定量构效关系模型.

关键词: Combretastatins类化合物, 定量构效关系, 遗传函数分析, 比较分子场分析, 比较分子相似因子分析

Abstract: The quantitative structure-activity relationship(QSAR) of a series of combretastatin analogues with ring B modification was studied. The two dimensional structure-activity relationship was carried out by genetic function analysis(GFA) method. The results indicate that Apol, PMI-mag, Dipole-mag, Hbond donor, and RadOfGyration descriptors contributed significantly to the activities. Furthermore, a three dimensional structure-activity was performed via comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA). An analyses of CoMFA and CoMSIA models resulted in a cross validated coeffieciency(q2) of 0.630 and 0.634 respectively, which showed a strong predictive ability. The contourmaps of CoMFA and CoMSIA provided smooth and interpretable explanation of the structure-activity relationship of the selected compounds. A molecular docking was used to analyze and validate the QSAR models. Those results provide a useful information to design novel tubulin inhibitors.

Key words: Combretastatin analogues, QSAR, Genetic function analysis, Comparative molecular field analysis, Comparative molecular similarity indices analysis

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