《抗糖尿病药物的虚拟筛选模型的设计》-毕业论文（设计）.doc

精品论文 = 1 \* ROMAN I 摘 要 糖尿病的发病率高、病情复杂、病程长、难根治等特点使其成为与心脑血管、肿瘤相并列的严重危害人类健康的3大病种之一。虚拟筛选已成为研发新药中的一个重要组成部分。近年来以PPARs为靶标的抗糖尿病药物出现了肝脏毒性、 水肿与心血管系统副作用、肾脏毒性、体重增加等毒副作用，这些药物大部分是PPARs的双重激动剂或三重激动剂，并且对于PPAR三种亚型中的δ亚型的研发较少。 基于这些问题，本课题研究者通过对已知药物及活性化合物与PPAR靶标的作用机理研究，运用分子模拟软件和分子对接软件GOLD，分别建立基于PPARα、δ、γ的三个药物虚拟筛选模型，对模型进行验证，并选取文献中一系列活性小分子与所建模型进行对接，计算结果与实验结果对比分析，改变计算条件进行实验结果分析。本课题研究者还研究了PPAR激动剂的结合方式。 本课题中建立的PPARα、δ、γ虚拟筛选模型能较好的重现激动剂的结合构象，选取的打分函数Goldscore和Chemscore都对较高活性的小分子有活性富集的作用。课题通过研究PPAR激动剂的结合方式，得到了如下结论：在PPAR激动剂的结合方式中氢键的形成起着重要的作用：与PPARα结合时要获得较高的激活活性，小分子的结构中一端需具有能与蛋白质残基SER280的OG原子、TYR314的OH原子、TYR464的OH原子、HIS440的NE2原子形成O-O型氢键或O-N型氢键的官能团；与PPARδ结合是时要获得较高的激活活性，小分子的结构中一端需具有能与蛋白质残基HIS323的NE2原子，TYR473的OH原子，HIS449的NE2原子，THR289的OG1原子形成O-O型氢键或O-N型氢键的官能团；与PPARγ结合是时要获得较高的激活活性，小分子的结构中一端需具有能与蛋白质残基HIS449的NE2原子，TYR473的OH原子，HIS323的NE2原子，SER289的OG原子形成O-O型氢键或O-N型氢键的官能团。 关键词：糖尿病，过氧化酶增殖体激活受体，虚拟筛选，分子对接 精品论文 = 2 \* ROMAN II ABSTRACT Diabetes has become one of three major diseases with its characteristics such as long and difficult to cure, high incidence, illness complicated. Virtual screening has become one of the important during drug development. Antidiabetic drugs whose targets are PPARs have some side effects such as lier toxicity,kidney toxicity.Most of these drugs are double agonists or triple agonists. The rd of PPAR delta from the three PPAR sub-types is less than the others . Based on these problems, this topic researcher through the research of mechanism between active compounds and PPARs establish three virtual screening models who based on PPARα、δ、γ sub-types with using molecular simulation software and molecular docking software. And then tested these models. The researchers also researched the way of the combination between the agonists and PPARs. The three virtual screening models which have been established in this topic can recreate a good combination of agonists conformation. The scoring functions Chemscore and Goldscore play a role of active enrichment during molecular docking.