物理化学学报 >> 2009, Vol. 25 >> Issue (05): 817-824.doi: 10.3866/PKU.WHXB20090505

研究论文 上一篇    下一篇

人类免疫缺陷病毒整合酶二酮酸类抑制剂的三维药效团构建

张小轶 刘斌 何红秋 杨东 王存新   

  1. 北京工业大学生命科学与生物工程学院, 北京 100124
  • 收稿日期:2008-12-10 修回日期:2009-01-22 发布日期:2009-05-04
  • 通讯作者: 王存新 E-mail:cxwang@bjut.edu.cn

Human Immunodeficiency Virus Integrase Pharmacophore Model Derived from Diketoacids Inhibitors

 ZHANG Xiao-Yi, LIU Bin, HE Hong-Qiu, YANG Dong, WANG Cun-Xin   

  1. College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, P. R. China
  • Received:2008-12-10 Revised:2009-01-22 Published:2009-05-04
  • Contact: WANG Cun-Xin E-mail:cxwang@bjut.edu.cn

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摘要：

应用遗传算法相似性程序(GASP), 以作用于I型人类免疫缺陷病毒(human immun-odeficiency virus type 1, HIV-1)整合酶(IN)的二酮酸类(diketoacids, DKAs)抑制剂构建药效团模型. 所选训练集分子均具有可靠的类药性特征及DKAs药效团特征. 尝试将抑制剂与药效团叠合后的构象和抑制剂与IN的对接构象进行叠合, 得到药效团模型与分子对接构象中IN残基的相对位置, 并基于抑制剂的药效团模型特征与周围IN氨基酸残基位置的匹配情况进行药效团特征的修改. 所得最优药效团由1个疏水特征、3对氢键特征和1个氢键供体特征组成. 该药效团的命中物质量(goodness of hit, GH)为0.56, 产出率(Y)达63.6%, 假阳性率(FP)为0.41%. 该药效团具有较好的置信度, 产出率较高而假阳性率较低, 可用于数据库搜索发现新的具有DKAs药效团特征的活性化合物, 也可为先导化合物的改造提供帮助.

关键词: 人类免疫缺陷病毒, 整合酶, 二酮酸类, 抑制剂, 药效团, 遗传算法相似性程序

Abstract:

We have developed a three-dimensional pharmacophore model for the human immunodeficiency virus type I (HIV-1) integrase (IN) from diketoacids (DKAs) inhibitors using the genetic algorithm similarity program (GASP). For the selected training set, reliable drug-like properties and DKA-like pharmacophore features exist. Inhibitor conformations were mapped into the pharmacophore model and superimposed in their docking conformations. Corresponding positions between the pharmacophore model and IN residues were thus obtained. The pharmacophore model was refined according to whether the pharmacophore features were compatible with residues around them. Finally, an optimal pharmacophore model was generated and consisted of 1 hydrophobic feature, 3 hydrogen pair features and 1 hydrogen-bond donor feature. The pharmacophore model had higher reliability with a goodness of hit (GH) score of 0.56, a high percentage yield of actives (Y) of 63.6%and a lower false positive rate (FP) of 0.41%. This pharmacophore model can contribute to the discovery and design of new DKA-like inhibitors.

Key words: Human immunodeficiency virus, Integrase, Diketoacides, Inhibitor, Pharmacophore, Genetic algorithmsimilarity program