毕业设计--抗糖尿病药物的虚拟筛选模型设计.doc

重庆大学本科学生毕业设计（论文） 抗糖尿病药物的虚拟筛选模型设计 学 生：李文慧 学 号： 指导教师：陈刚 专 业：药学 重庆大学化学化工学院 二O一一年六月 Graduation Design(Thesis) of Chongqing University Virtual Screening Model Design for Antidiabetic Drug Undergraduate: Li Wenhui Supervisor: Chen Gang Major: Pharmacy College of Chemistry and Chemical Engineering Chongqing University June 2011  摘 要 糖尿病发病率高、病情复杂、病程长、难根治等特点成为与心脑血管、肿瘤相并列的严重危害人类健康的3大病种之一。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，本课题研究者通过合α、δ、γ，本课题还研究的α、δ、γGoldscore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激动剂的的α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  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 molecula