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S. Sakkiah, S. Thangapandian, S. John, et al. 3D QSAR phar- macophore based virtual screening and molecular docking for identification of potential HSP90 inhibitors. European Journal of Medical Chemistry, 2010, 45(6): 2132-2140.

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  • 标题: 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, 谷俊峰, 曹志, 赵伟杰, 王希诚

    关键字: Ⅱ型糖尿病, 二肽基肽酶Ⅳ, 药效团模型, 数据库搜索TypeⅡ Diabetes; Dipeptidyl-Peptidase IV; Pharmacophore Model; Database Searching

    期刊名称: 《Hans Journal of Chemical Engineering and Technology》, Vol.2 No.2, 2012-04-19

    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.

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