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化学学报
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化学学报 ›› 2008, Vol. 66 ›› Issue (20): 2209-2218. 上一篇    下一篇

研究论文

Discodermolide及其衍生物三维定量构效关系的研究

张 伟a 李 婕b 李艳妮*,a

  

  1. (a天津大学化工学院制药工程系 天津 300072)
    (b中国科学院上海有机化学研究所 上海 200032)

  • 投稿日期:2008-01-21 修回日期:2008-05-07 发布日期:2008-10-28
  • 通讯作者: 李艳妮

Three-Dimensional Quantitative Structure-Activity Relationship Studies on Discodermolide and Its Derivatives

ZHANG, Wei a LI, Jie b LI, Yan-Ni *,a   

  1. (a Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology,
    Tianjin University, Tianjin 300072)
    (b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032)
  • Received:2008-01-21 Revised:2008-05-07 Published:2008-10-28
  • Contact: LI, Yan-Ni

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Discodermolide是一种新颖的作用于微管蛋白的抗肿瘤化合物, 具有良好的药用前景. 为了设计出药效更好的类似物, 我们用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)对discodermolide及其衍生物进行了三维定量构效关系(3D-QSAR)的研究, 并建立了相关的预测模型. 其中, CoMFA模型的交叉验证相关系数(q2)为0.592, 非交叉验证相关系数(r2)为0.982, 标准偏差(SEE)为0.094, F值为119.761; CoMSIA模型的q2为0.544, r2为0.980, SEE为0.098, F值为108.715. 计算结果表明, 获得的CoMFA和CoMSIA模型具有良好的预测能力, 可以应用于指导该类化合物的设计.

关键词: discodermolide, 三维定量构效关系, 微管蛋白

Discodermolide, which acts on tubulin, is a novel and anti-tumor compound. It has good pharmaceutical prospect. For purpose of designing more potent analogues, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on discodermolide and its derivatives using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). The best predictions were obtained with the CoMFA steric, electrostatic fields (leave-one-out q2＝0.592, no validation r2＝0.982, standard error of estimate＝0.094, F＝119.761), and with the CoMSIA combined electrostatic, hydrophobic, H-bond donor and acceptor fields (leave-one-out q2＝0.544, no validation r2＝0.980, standard error of estimate＝0.098, F＝108.715). Our results show that the obtained CoMFA and CoMSIA models have good predict ability, which can be used for designing of homologic compounds.

Key words: discodermolide, 3D-QSAR, tubulin