基于AMPK为靶点的吲哚羧酸类新型胰岛素增敏剂的设计、合成的研究

发布时间：2018-06-17 01:17

本文选题：AMPK + GY3　；参考：《贵阳医学院》2014年博士论文

【摘要】：目的2型糖尿病和代谢紊乱综合征越来越危害人类的健康,因此迫切需要研发能改善胰岛素抵抗和高糖血症的药物。然而,寻找与糖尿病相关的作用靶点是近年来糖尿病领域的研究热点,腺苷酸激活蛋白激酶(AMP-activated protein kinase, AMPK)是一系列蛋白激酶中的关键部分,同时参与机体糖代谢、脂代谢、蛋白代谢、心血管等多个方面的调控,并且在能量的感应中起着关键的作用。所以,合成能够激动AMPK靶点的新型化合物将是开发抗2型糖尿病药物的重要研究方向。方法项目组在前期研究工作中发现化合物GY3、ZG05等具有较好的胰岛增敏活性,通过计算机药物辅助设计中的三雏模拟对接及打分,药效团模型综合对具有一定胰岛素增敏活性的化合物进行了优化设计。本论文以GY3、ZG05为先导化合物主要进行了以下两方面的研究工作：1.①对GY3中吲哚环1-位的酰胺键进行结构改造,共设计了7个化合物。②在吲哚2,3-位双键还原的基础上,对1位进行改造,设计1个化合物。③在吲哚3-位碳链延长为丁酸的基础上,对1-位的酰胺键进行结构改造,共设计了5个化合物。④在吲哚2,3-位双键还原的基础上对3位的羧酸进行改造,共设计了17个化合物。2.对合成出的化合物进行HepG2细胞葡萄糖消耗实验,测试化合物是否具备体外胰岛素增敏活性。3.对合成出的化合物的三维空间构型与抗2型糖尿病的靶点AMPK受体进行对接。结果通过上述研究工作,本论文主要设计了4条研究路线,合成出了30个化合物,经SciFinder检索均为首次合成。结论通过配体受体的相互作用模式图可知,作为AMPK的激动剂,GY3及其衍生物与受体的相互作用主要集中在结合口袋中的氨基酸Lys45、Asn67、Cys130、Arg138、 Leu140、Lys141、Ile155这些结合位点上面,氢键作用主要产生于配体分子中的羧基和苯环,疏水作用则主要产生于吲哚环以及吲哚环上的甲基。可能为以后研究开发基于AMPK靶点的抗2型糖尿病药物提供一定的理论指导。
[Abstract]:Objective Type 2 diabetes mellitus and metabolic disorder syndrome are more and more harmful to human health, so it is urgent to develop drugs to improve insulin resistance and hyperglycemia. However, searching for targets related to diabetes is a hot topic in recent years. Adenylate activated protein kinase AMP-activated protein kinase (AMPK) is a key part of a series of protein kinases, which is involved in glucose metabolism and lipid metabolism. Protein metabolism, cardiovascular and other aspects of regulation, and play a key role in energy sensing. Therefore, the synthesis of novel compounds that can excite AMPK targets will be an important research direction in the development of anti-diabetic drugs. Methods in the previous research work, the project group found that the compound GY3OZG05 had better islet sensitizing activity. The pharmacophore model was used to optimize the design of compounds with certain insulin sensitizing activity. In this thesis, the structure of indole-ring 1-site amide bond in GY3 was modified by using GY3OZG05 as the leading compound. Seven compounds .2 were designed on the basis of the reduction of indole _ 2o _ 3-position double bond. One site was modified, and a compound .3 was designed to reconstruct the 1-site amide bond on the basis of the extension of the indole-3-site carbon chain to butyric acid. A total of 5 compounds were designed to modify the 3-position carboxylic acid on the basis of indole 2o 3-site double bond reduction, and a total of 17 compounds .2. were designed. The glucose consumption of the synthesized compounds in HepG2 cells was tested to determine whether the compounds had insulin sensitizing activity in vitro. 3. The three-dimensional spatial configuration of the synthesized compounds was linked to AMPK receptor, a target of anti-type 2 diabetes mellitus. Results through the above research work, four main research routes were designed and 30 compounds were synthesized, which were all synthesized for the first time by SciFinder. Conclusion the interaction pattern of ligand receptor shows that the interaction between GY3 and its derivatives as agonist of AMPK is mainly located at the binding sites of amino acids Lys 45, Asn 67, Cys 130, Arg138, Leu140, Lys141 and Ile155 in the binding pocket. Hydrogen bonds are mainly produced by carboxyl groups and benzene rings in ligand molecules, while hydrophobic interactions mainly occur in indole ring and methyl group on indole ring. It may provide some theoretical guidance for the future research and development of anti-type 2 diabetes drugs based on AMPK targets.
【学位授予单位】：贵阳医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R91

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