G-Coupled Protein Receptor 81(GPR81)agonists can play the efficacy of GPR109A agonists in the treatment of dyslipi-demia to reduce its side effects. However,GPR81 is an important membrane protein and its three-dimensional structure is still un-clear. In such case,the role of GPR81 and the interaction mechanism with its agonists are still difficult to be illustrated clearly. In this paper,based on the primary structure of GPR81,the tertiary structure of GPR81 protein was constructed by homology modeling method. Evaluated the model by the Ramachandran Plot and Profile-3D,optimized the model with the molecular dynamics and loop optimization,finally we obtained one stabile three-dimensional structure protein model and found eight cavities which might be the active sites in the optimal model. The potential GPR81 pyrazole agonist molecules were constructed and then optimized by the stee-pest descent method and the conjugate gradient method to receive the most stable conformation. All the agonists were docked into each active site of the protein by Libdock method,which supports the process of receiving interaction models and interaction scores. Furthermore,in this experiment we analyzed the composition of amino acids of each active site with 3-hydroxy benzoic acid as a ref-erence drug molecule to explore the interaction force. The G-coupled Protein Receptor 81 model and the interaction model of the protein with dihydroxy-benzoic acid agonists have theoretical significance for designing the agonists of the membrane protein.%G蛋白偶联受体81(GPR81)激动剂不仅可以发挥出GPR109A激动剂治疗血脂障碍的功效,还可降低副作用,但GPR81属于膜蛋白且三维结构未知,其与药物作用情况仍难以解析.本文基于已知的GPR81一级序列,采用同源模建的方法构建GPR81蛋白三维结构,运用拉氏图和Profile-3D对模型进行评估,通过分子动力学,加膜,loop环区等方法对模型进行优化,得到蛋白最优模型,模型Verify Score为130.27(预期Verify Score值区间为60.8112~135.136),并计算分析得到8个可能的活性位点.构建GPR81的苯甲酸类激动剂药物小分子,通过最陡下降法和共轭梯度法获得药物分子最低能量构象.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-羟基-苯甲酸类药物作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GPR81苯甲酸类激动剂有理论指导意义.
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