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化学学报
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化学学报 ›› 2005, Vol. 63 ›› Issue (15): 1409-1414. 上一篇    下一篇

研究论文

评估石杉碱甲杂合体衍生物作为AD症药物活性顺序的简单方法

韩大雄，杨频*   

  1. (山西大学分子科学研究所 化学生物学与分子工程教育部重点实验室 太原 030006)
  • 投稿日期:2004-05-11 修回日期:2005-04-02 发布日期:2010-12-10
  • 通讯作者: 杨频

A Practical Method for Ranking Inhibitory Activity of Huprine X Derivatives on Acetylcholinesterase via Binding Free Energy Calculations

HAN Da-Xiong, YANG Pin*   

  1. (Institute of Molecular Science, Shanxi University, Key Laboratory of Chembiolody and Molecular Engineering of the Ministry of Education, Taiyuan 030006)
  • Received:2004-05-11 Revised:2005-04-02 Published:2010-12-10
  • Contact: YANG Pin

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1035

被引次数

4

为了合理化设计、指导具有高活性、低毒性的石杉碱甲杂合体(Huprine X)衍生物的合成, 建立了一个计算结合自由能的新方案, 以实现对该类衍生物活性排列顺序的预测. 该结合自由能由三部分组成: 抑制剂和靶酶的相互作用能; 活性位点残基在结合前后的构象绝对自由能的变化; 抑制剂从稳定构象变为活性构象的自由能增加值. 通过计算已合成的14个杂合体衍生物的结合自由能, 结果显示理论值和实验测定的生物活性值有很好的等级相关性, 其斯皮尔曼相关系数为0.85, 证明了该方法的可行性.

关键词: 结合自由能, 石杉碱甲杂合体, 乙酰胆碱脂酶, 分子动力学

In order to design novel tacrine-huperzine A hybrid (Huperzine X) derivatives, a new practical proposal was built to calculate binding free energy. The method assumed that the free energy of binding was cast simply as a linear combination of three descriptors: interaction energy between inhibitors and protein, the difference in the absolute conformation free energy of protein between the bound and unbound states, and the free energy increase of inhibitors from the stabilized conformation to activity conformation. For the total of 14 huperzine X derivatives, the result obtained from the method was found to correlate well to the inhibitory activity IC50 for acetylocholinesterases with the Spearman's correlation coefficient rs＝0.85.

Key words: binding free energy, huperzine X, acetylocholinesterase, molecular dynamics