物理化学学报 >> 2006, Vol. 22 >> Issue (03): 359-364.doi: 10.3866/PKU.WHXB20060321

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γ-分泌酶抑制剂的药效团模型构建

鄢浩; 姜凤超   

  1. 华中科技大学同济医学院药学院, 武汉 430030
  • 收稿日期:2005-08-09 修回日期:2005-10-07 发布日期:2006-03-10
  • 通讯作者: 姜凤超 E-mail:fengchao@mails.tjmu.edu.cn

Pharmacophore Model Construction of γ-secretase Inhibitor

YAN Hao; JIANG Feng-Chao   

  1. School of Pharmacy, Tongji Medical College of Huazhong Science & Techology University, Wuhan 430030, P. R. China
  • Received:2005-08-09 Revised:2005-10-07 Published:2006-03-10
  • Contact: JIANG Feng-Chao E-mail:fengchao@mails.tjmu.edu.cn

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摘要： 利用Catalyst软件系统, 选择具有较高体外抑制活性的苯并二氮(艹卓)类化合物作为训练集, 经计算机建模, 构象优化, 由Catalyst系统构建出药效团模型. 并结合γ-分泌酶的作用机制等因素, 筛选出一个含有一个芳环中心, 一个疏水中心和两个氢键受体的具有较好预测能力(RMS=0.366343, Correl=0.95535, Weight=1.17389, Config=18.8671)的药效团模型. 该模型的建立有助于设计及合成新型结构的γ-分泌酶抑制剂.

关键词: 阿尔茨海默病, 计算机辅助药物设计, γ-分泌酶抑制剂, 药效团

Abstract: The pharmacophore model of γ-secretase inhibitors was established by the Catalyst software with the training set of Benzodiazepine-based γ-secretase inhibitors. Based on the action mechanism and the known structure-activity relationship, a fitting pharmacophore model (RMS=0.366343, Correl=0.95535, Weight=1.17389, Config=18.8671) including two hydrogen-bonding acceptors, an aliphatic hydrophobic core and an aromatic ring center, was confirmed. This pharmacophore model will contribute to the design and synthesis of new-type γ-secretase inhibitors.

Key words: Alzheimer′s disease, Computer-aided drug design, γ-secretase inhibitor, Pharmaophore