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化学学报
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化学学报 ›› 2008, Vol. 66 ›› Issue (16): 1889-1897. 上一篇    下一篇

研究论文

β分泌酶抑制剂的药效团模型研究

黄文海 胡纯琦 廖 勇 盛 荣 胡永洲*

  

  1. (浙江大学巴黎高等师范学院药物化学联合实验室 浙江大学药学院 杭州 310058)

  • 投稿日期:2007-11-20 修回日期:2008-03-24 发布日期:2008-08-28
  • 通讯作者: 胡永洲

Pharmacophore Model Construction of β-secretase Inhibitors

HUANG, Wen-Hai HU, Chun-Qi LIAO, Yong SHENG, Rong* HU, Yong-zhouZhou*

  

  1. (Zhejiang University-Ecole Normale Superieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Science,
    Zhejiang University, Hangzhou 310058)
  • Received:2007-11-20 Revised:2008-03-24 Published:2008-08-28
  • Contact: HU, Yong-zhouZhou

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1460

被引次数

14

选择活性跨越0.002至25 μmol•L－1的4类共25个β分泌酶抑制剂作为训练集, 使用Catalyst软件包构建出药效团模型, 并通过对药效团的有效性分析, 筛选得到的最佳模型(correlCorrel＝0.969, Config＝16.32, Δcost＝62.422)由一个环芳香性、一个疏水中心、一个正电荷中心和一个氢键供体组成. 并用其它209个抑制剂组成测试集对模型进行验证, 结果表明该模型显示出较强的预测能力, 能够为进一步的数据库搜索, 寻找新型的β分泌酶抑制剂先导物提供依据.

关键词: 药效团模型, β分泌酶, 非肽类抑制剂

Pharmacophore models of β-secretase inhibitors were developed by using Catalyst HypoGen program with a training set of 25 compounds (IC50 values from 0.002μmol·L-1 to 25 μmol•L－1) containing 4 different kinds of structures. A fitting pharmacophore hypothesis (Ccorrel＝0.969, Config＝16.32, Δcost＝62.422) was characterized by one aromatic ring center, one aliphatic hydrophobic core, one pos positively ionizable center and one hydrogen bond donor. The model was applied in to predicting the activity of other 209 inhibitors as a test set. The result indicates that the pharmacophore model exhibits good predictive ability and is able to provide clear guidelines for screening new lead compounds of β-secretase inhibitors.

Key words: pharmacophore model, β-secretase, nonpeptidomimetic inhibitor