γ分泌酶抑制剂的药效团模型构建.pdf

物理化学学报(Wuli Huaxue Xuebao) March Acta Phys. Chim. Sin., 2006, 22(3) ：359 364 359 [Note] 分泌酶抑制剂的药效团模型构建 浩 姜凤超* (华中科技大学同济医学院药学院, 武汉 430030) 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 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 鄄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 鄄分泌酶抑制 . 关键词： 阿尔茨海默病, 计算机辅助药 设计, 鄄分泌酶抑制 , 药效团 中图 类号： O641 Pharmacophore Model Construction of secretase Inhibitor YAN, Hao JIANG, Feng鄄Chao* (School of Pharmacy, Tongj i Medical College of Huazhong Science Techology University, Wuhan 430030, P. R. China) Abstract The pharmacophore model of 鄄secretase inhibitors was established by the Catalyst software with the training set of Benzodiazepine鄄based 鄄secretase inhibitors. Based on the action mechanism and the known structure鄄 activity relationship , a fitting pharmacophore model (RMS=0 .366343 , Correl=0 .95535, Weight = 1.17389 , Config= 18.8671) including two hydrogen鄄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鄄type 鄄secretase inhibitors. Keywords ： Alzheimer忆s disease, Computer鄄aided drug design, 鄄secretase inhibitor, Pharmaophore 阿尔茨海默病(Alzheimer 忆s disease, AD)是老年 (presenilin, PS) 、单过性跨膜蛋白(Nicastrin, NCT)、整 人常见的神经系统变性疾病, 又称老年痴呆症, 是 膜蛋白APH鄄1 和PEN鄄2 (presenilin enhancer鄄2, PEN鄄 一种中枢神经系统原发性退行性病变, 患者进行性