GPR109A同源建模及其与吡唑类激动剂对接模拟

Homology modelling of G-coupled protein receptor 109A and docking simulation with pyrazole agonists

烟酸受体G偶联蛋白受体109A(GPR109A)是心血管疾病和脂代谢紊乱等疾病治疗的重要靶点蛋白,但因属于膜蛋白,其晶体结构一直未被解析,给药物设计带来极大挑战。本文基于鼠类PUMA-G晶体结构,采用同源模建的方法构建GPR109A蛋白三维结构,运用Ramachandran Plot和Profile-3D对模型进行评估,通过加力场,加膜,loop等方法对模型进行优化,得到蛋白最优模型,并计算分析得到其12个可能的活性位点。利用SYBYL-X2软件构建GPR109A的吡唑类激动剂药物小分子,通过最陡下降法和共轭梯度法得到药物小分子的最稳定构象。用Libdock方法将激动剂对接至蛋白各活性位点,获得二者作用模型。我们分析各活性位点氨基酸分布情况,并以3-羧酸5-甲基吡唑为参考分子探讨药物与各蛋白活性位点相互作用情况。本实验对设计G偶联蛋白受体109A吡唑类激动剂有理论指导意义。

Niacin receptor g-coupled protein receptor 109A （GPR109A） is an important target protein of the treatment of Cardiovascula diseases and disorders of lipid metabolism diseases. Since GPR109A is one membrane protein whose crystal structure has not been resolved, there are many challenges to drug design on the receptor. Based on the mouse PUMA-G crystal structure, the three dimensional structure of GPR109A was built by using homology modeling method. Evaluated the model by using the Ramachandran Plot and Profile-3D, optimized the model with MMFF94 forcefield, membrane, and method of loop, finally we obtained one stabile model and found 12 sites which might be the active sites in the optimal model. SYBYL-X2 software was used to build GPR109A pyrazole agonist drug molecules, through the steepest descent method and the Conjugate gradient method to receive the most stable conformation of the small drugs molecules. All the agonists were docked into each active site of the protein by Libdock method, receiving the interaction models. We analyzed the distribution of amino acid of each active site, and took 5-methyl-3-carboxylic acid as a reference drug molecule to explore the interaction force with each protein active site. This study has theoretical significance in designing G-coupled protein receptor 109A pyrazole agonists.