新型降糖药PPARα_γ双重激动剂的设计.docVIP

  新型降糖药 PPARα/γ双重激动剂的设计# 马英1，王润玲1，王树青1，徐为人2** （1. 天津市临床药物关键技术重点实验室，天津医科大学药学院，天津 300070； 5 10 2. 天津药物研究院，天津 300193） 摘要：目的：设计过氧化物酶体增殖因子活化受体(PPAR)激动剂。方法:应用“Core Hopping” （骨架替换）模块对 PPAR 双重激动剂 GW409544 进行结构改造，构建了 PPAR 激动剂的虚拟 化合物库，然后利用 Schrodinger Suite2009 构建小分子化合物库、蛋白结构优化、分子对 接、分子动力学模拟和 ADME 预测。结果：设计出一系列新的 PPAR 双重激动剂。用分子对接 方法和分子动力学模拟分析了新激动剂和 PPAR α/γ的相互作用机制，与已有的激动剂相 比有了更好的结合能力。结论：设计小分子与 PPAR α/γ的结合能力理论上优于原始配体。 可能会是一个很好的治疗 II 型糖尿病的双重激动剂。 关键词：PPAR；双重激动剂；药物设计；分子动力学；ADME 中图分类号：R914.2 15 Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors MA Ying1, WANG Runling1, WANG Shuqing1, XU Weiren2 (1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and 20 25 30 35 40 Diagnostics (Theranostics) ，School of Pharmacy, Tianjin Medical University, TianJin 300070; 2. Tianjin Institute of Pharmaceutical Research, TianJin 300193) Abstract: Objective: To develop peroxisome proliferator-activated receptors α/γ novel dual agonists. Methods: In this study, by means of the powerful core hopping, a novel class of PPAR dual agonists was discovered based on the compound GW409544.Then, the small molecular library，protein structure optimization ,molecular docking and ADME predictions were carried out using soft ware Schrodinger Suite 2009.Results： It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. Conclusion: The binding affinity of the designed molecules is theoretically higher than the original ligand in PPARα/γ.It is anticipated that the new agonists may become potential drug candidates. Keywords: PPAR; dual agonists; computer aid design drug; molecular docking; ADME 0 引言 糖尿病被列为继心血管疾病及肿瘤之后的第三大疾病，因此研究新型降糖药已迫在眉 睫。目前全世界糖尿病患者中大部分是 II 型糖尿病，主要问题是胰岛素抵抗[1]。最近几年， 研究人员发现，过氧化物酶体增殖因子活化受体(PPAR)配体激活转录因子，可调节许多基 因的表达，影响血