毒蕈碱型M_1受体的同源模建和分子对接

Homology Modeling and Molecular Docking on Muscarinic M_1 Receptor

采用同源模建方法对M1受体的三维结构进行了模拟,将得到的模型分别与M受体完全激动剂乙酰胆碱和M1受体选择性激动剂占诺美林进行分子对接,形成非特异性激动和特异性激动的受体-配体复合物.用分子动力学模拟方法分别将未与小分子对接的M1受体、M1受体-乙酰胆碱复合物、M1受体-占诺美林复合物置于磷脂双膜中模拟10ns.将模拟后的蛋白质结构与包含活性分子的测试库对接并将结果打分,以top5%富集因子(EF)作为评价依据,用占诺美林优化后的M1受体模型的EF为8.0,用乙酰胆碱优化后M1受体模型的EF为6.5,非复合物的EF为1.5.说明M1受体选择性激动剂复合物进行分子动力学模拟后得到的三维结构模型比较合理,可以作为化合物虚拟筛选的模型对新化合物进行虚拟筛选,为找到新的选择性M1受体激动剂奠定了基础.

Three-dimensional structure model of MI receptor was built through homology modeling. M receptor full agonist acetylcholine （ACh） and Mj receptor selective agonist xanomeline were docked into the model protein to form receptor-ligand complexes. Those complexes together with a receptor protein were put into a phospholipid bilayer for a 10 ns molecular dynamics （MD） simulation. Numbers of known active molecules were scattered into randomly selected databases, and the ACh compounds were docked with a model protein and ranked by their docking scores. The best model protein with the highest enrichment factor （EF） was chosen. The EF of the top5% of the active molecules for the chosen M~ protein receptor-xanomeline docking complex, the receptor-acetylcholine complex, and the non-complex were 8.0, 6.5, and 1.5, respectively. These results indicate that optimization of structures by MD simulation of M1 selective ligand-receptor is reasonable for virtual screening. The optimized M1 receptor protein structure can be used for virtual screening and for novel design to discover more potent compounds.