GPR40激动剂作用方式及药效团模型研究

Study on the mode of action and pharmacophore model of GPR40 agonists

为阐明GPR40与其激动剂分子之间的相互作用方式,构建可用于GPR40激动剂分子先导化合物筛选的药效团模型。我们利用分子对接技术将GPR40与其激动剂分子进行对接,分析分子与受体之间相互作用的关键氨基酸和结合方式,采用药团模型法分别构建了基于受体 配体复合物(CBP)和基于激动剂分子共同特征(HipHop)的药效团模型,HipHop模型采用测试集法进行验证。结果显示GPR40与小分子相互作用的关键氨基酸主要有ARG183、TYR91、TYR2240、ARG2258、PHE142等,相互作用方式则主要为氢键、盐桥、Pi-Pi Stacking以及疏水作用,以药团模型法构建了10个HipHop模型,其中8号药效团为最优模型,可用于GPR40激动剂分子的虚拟筛选研究,这为GPR40激动剂药物分子设计奠定了理论基础。

To elucidate the interaction between GPR40 and its agonist molecules,and to construct a pharmacophore model for screening GPR40 agonist molecular lead compounds.We using molecular docking technology to dock GPR40 with its agonist molecules,and analyze the key amino acids and combinations of interactions between molecules and receptor,the Receptor-Ligand Pharmacophore model(CBP)and Common Feature Pharmacophore model(HipHop)were constructed using the pharmacophore modeling method,the HipHop model is validated by test set method.The results show that the key amino acids interacting with GPR40 and small molecules are ARG183,TYR91,TYR2240,ARG2258,PHE142,etc,the interaction modes are mainly hydrogen bonding,salt bridge,Pi-Pi Stacking and hydrophobic interaction,ten HipHop models were constructed by the pharmacophore modeling method,in which the No.8 pharmacophore was the optimal model,it can be used for the virtual screening studies for GPR40 agonist molecules,which lays a theoretical foundation for the molecular design of GPR40 agonist drugs.