GPR40激动剂药效团模型的构建及验证

Development and validation of pharmacophore of G protein-coupled receptor 40 agonists

目的:构建和验证GPR40激动剂药效团模型。方法:采用生物活性跨越1~160000 nmol?L^(-1)的23个GPR40激动剂小分子作为训练集进行药效团模型的构建;利用测试集验证、Fisher验证及分子对接方法对模型进行评价;根据所构建的药效团模型,设计并合成2个全新结构的化合物,通过正常小鼠糖耐量试验的验证。结果:筛选得到由1个氢键受体(HBA)、2个疏水中心(HP)、1个芳环中心(RA)组成的最佳模型(Correl.=0.971,Config=16.645,△cost=58.370),依据药效团模型设计得到的与药效团匹配较高的化合物Lyb-438能显著降低正常小鼠餐后0.5 h血糖(P<0.05)。结论:所构建的药效团模型具有较强的预测能力和较高的可信性,为进一步的数据库搜索及寻找新型小分子GPR40激动剂提供了依据。

G protein coupled receptor 40（GPR40）, which plays a vital role in glucose equilibrium, has become one of potential targets for type 2diabetes （T2D） pharmacotherapy. Pharmacophore models were developed by using Discovery Studio with a training set of 23 GPR40 agonists using Discovery studio 3.0. The best hypothesis consisting of four features, namely, one hydrogen bond acceptors, two hydrophobic features and one ring aromatic feature, has a correlation coefficient of 0.971, cost difference of 58.37, RMS of 0.971, and configuration cost of 16.645. This model was validated by the test set, Fischer randomization test and Dock Ligands. According to pharmacophore model, two new compounds were designed and synthesized to evaluate the hypoglycemia activity. Compounds Lyb-438 that fit to pharmacophore model could significantly decrease the blood glucose level of normal mice （P〈0.05）. The estab- lished pharmacophore model has good predictive ability and can be further used to develop novel GPR40 agonists.