物理化学学报 >> 1998, Vol. 14 >> Issue (10): 887-892.doi: 10.3866/PKU.WHXB19981006

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凝血酶抑制剂的结构与活性的关系

王任小, 刘亮, 来鲁华, 唐有祺   

  1. 北京大学物理化学研究所，北京 100871
  • 收稿日期:1997-12-24 修回日期:1998-04-20 发布日期:1998-10-15
  • 通讯作者: 王任小

Structure-Affinity Relationship of Thrombin inhibitors

Wang Ren-Xiao, Liu Liang, Lai Lu-Hua, Tang You-Qi   

  1. Institute of Physical Chemistry,Peking University,Beijing 100871
  • Received:1997-12-24 Revised:1998-04-20 Published:1998-10-15
  • Contact: Wang Ren-Xiao

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摘要：

应用了一种新的预测酶－配体复合物亲和性的方法来研究凝血酶抑制剂的结构－活性关系．凝血酶－抑制剂复合物的三维结构根据模板化合物的晶体结构进行搭建，然后使用程序SCORE计算复合物的亲和性．共分析了3个系列34个抑制剂分子．计算所得的复合物的解离常数与实验值吻合得很好，大大优于用分子力学所给出的结果．通过比较其中两个抑制剂分子的结构和活性，说明了此方法能够定量给出配体分子中每个原子对结合过程的贡献大小，给出十分直接的结构－活性关系．

关键词: 凝血酶抑制剂, 亲和性, 基于结构的定量构效关系, 药物设计

Abstract:

A new method which can estimate the binding affinity of an enzyme-ligand complex was applied to studying the inhibitors of thrombin. The three-dimensional structures of thrombininhibitor complexes were modeled from the crystalline structures of template compounds. Program SCORE was then used to predict the binding affinities of the complexes. Altogether 34 inhibitors of three series were analyzed. The calculated dissociation constants correlated well with the experimentally determined values. This result is much better than the ones given by standard molecular mechanics. By comparing the structures and the binding affinities of two inhibitors, it was demonstrated that this method could measure the contribution of each part of a ligand quantitatively and in turn give explicit structrue-activity relationships.

Key words: Thrombin inhibitor, Binding affinity, Structure-based quantitative structure-activity relationship, Drug design