DPP-Ⅳ抑制剂三维药效团模型构建  

3D Pharmacophore Model Construction of DPP-Ⅳ Inhibitors

作　　者：韩天佼 李悦青[1] 谷俊峰[2] 曹志 赵伟杰[1] 王希诚[2] 

机构地区：[1]大连理工大学制药科学与技术学院,大连 [2]大连理工大学工业装备结构分析国家重点实验室,大连

出　　处：《化学工程与技术》2012年第2期53-60,共8页Hans Journal of Chemical Engineering and Technology

基　　金：国家重点基础研究发展计划(973)项目,批准号:2009CB918501。

摘　　要：以20个文献报道的二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂作为训练集,利用Discovery Studio构建了DPP-Ⅳ抑制剂的三维药效团模型。所得最优药效团模型Hypo1具有一个氢键受体,一个疏水基团,一个可离子化正电中心,一个芳香环和5个排除体积,Fischer交叉验证结果表明该模型具有较高的置信度。Hypo 1对测试集中20个DPP-Ⅳ抑制剂活性进行了预测,结果显示有较好的预测能力。利用该模型进行ZINC数据库搜索,得到预测活性小于10 nmol?L–1的化合物1369个。将这些化合物对接到DPP-Ⅳ的活性位点并根据PLP2评分函数筛选出21个评分较高的化合物,为设计和合成新型的DPP-Ⅳ抑制剂提供了理论参考。The 3D pharmacophore model of DPP-Ⅳ inhibitors was established using the Discovery Studio software with the training set of 20 DPP-Ⅳ inhibitors. The best pharmacophore hypothesis (Hypo 1) consists of one hydro- gen-bond acceptor, one hydrophobic point, one positive ionizable group, one aromatic ring as well as five excluded volumes. Fischer’s validation clearly shows that proposed Hypo 1 has highly predictive ability and can be efficiently used as a 3D query for virtual screening to retrieve potential inhibitors from ZINC databases. The hit compounds sub- sequently were docked into the DPP-Ⅳ active site and 21 compounds were obtained based on PLP2 scoring function. Therefore, this study could provide scientific basis for denovo design of DPP-Ⅳ inhibitors.

关 键 词：Ⅱ型糖尿病 二肽基肽酶Ⅳ 药效团模型 数据库搜索 

分 类 号：R73[医药卫生—肿瘤]