量热法与光谱法研究FTO蛋白与小分子类似物的相互作用

发布时间：2018-02-28 11:18

本文关键词： 结构类似物 FTO蛋白光谱法等温滴定量热法相互作用　出处：《郑州大学》2017年硕士论文　论文类型：学位论文

【摘要】：FTO(fat mass and obesity associated)是与肥胖有关的基因,可通过去甲基作用来影响其他基因的表达。目前对于FTO蛋白是否为有效的药物作用靶点还不是很清楚,而药物小分子与蛋白质的作用情况可在一定程度上预示药物作用的发展进程,因此,对于FTO蛋白与小分子类似物相互作用的研究有助于筛选有效的FTO抑制剂,指导药物先导化合物的优化及设计。本论文采用量热法及光谱法研究了咔唑类生物碱、核苷类似物、喜树碱及其衍生物、三氮唑衍生物与FTO蛋白的相互作用,主要分为以下几个部分:第一章:主要概述了蛋白质的结构功能、药物小分子与蛋白质大分子相互作用的研究方法、内容及意义。第二章:采用量热法、光谱法及分子模拟研究了6种咔唑生物碱(2a~2f)与FTO蛋白的结合情况,结果显示:只有化合物2e与FTO发生了结合,结合过程为静态猝灭,静电力和疏水作用为主要作用力,同时FTO蛋白的构象发生了变化。第三章:采用光谱法及分子模拟法研究了6种核苷类似物(3a~3f)与FTO蛋白的相互作用情况,结果表明:6种核苷类似物均能通过静态猝灭过程与FTO发生相互作用,同时疏水作用占主导作用,温度升高会引起复合物稳定性升高;与其他化合物相比化合物3d和FTO的结合能力最强。第四章:研究了FTO蛋白与3种喜树碱及其衍生物(4a~4c)的相互作用。3种化合物都能使FTO蛋白的荧光发生静态猝灭,静电力和疏水作用为分子间主要作用力,取代基种类及位置都会影响反应结果,三个反应体系中化合物4b与FTO蛋白的结合能力最强。第五章:考察了6种三氮唑衍生物(5a~5f)与FTO蛋白的相互作用。6种三氮唑衍生物引起FTO蛋白猝灭的过程为静态猝灭,疏水作用力为主要作用力,其中化合物5a与5f的结合常数较大,化合物5c最小,分子模拟结果与光谱学结果基本一致。
[Abstract]:FTO(fat mass and obesity is a fat-related gene that affects the expression of other genes through demethylation. It is not clear whether the FTO protein is an effective drug target. However, the interaction between small molecules and proteins may to some extent indicate the development of drug action. Therefore, the study of the interaction of FTO proteins with small molecular analogues may help to screen effective FTO inhibitors. In this paper, the interaction of carbazole alkaloids, nucleoside analogues, camptothecin and its derivatives with FTO protein was studied by calorimetry and spectrophotometry. It is mainly divided into the following parts: the first chapter: the structure and function of protein, the research methods, contents and significance of the interaction between small drug molecules and protein macromolecules. The binding of six carbazole alkaloids (2a2f) to FTO protein was studied by spectrophotometry and molecular simulation. The results show that only compound 2e binds to FTO, the binding process is static quenching, and hydrostatic and hydrophobic interaction is the main interaction force. At the same time, the conformation of FTO protein was changed. In Chapter 3, the interaction of six nucleoside analogues with FTO protein was studied by spectrophotometry and molecular simulation. The results showed that all of the six nucleoside analogues could interact with FTO through static quenching process, and the hydrophobic interaction was dominant, and the stability of the complex would be increased with the increase of temperature. Compared with other compounds, compounds 3D and FTO have the strongest binding ability. Chapter 4th: we studied the interaction of FTO protein with three camptothecin and its derivative (4a4c). 3 kinds of compounds can cause the fluorescence of FTO protein to be quenched statically. Electrostatic force and hydrophobic interaction are the main intermolecular forces, and the type and position of substituents will affect the reaction results. The binding ability of compound 4b to FTO protein was the strongest in the three reaction systems. Chapter 5th: the interaction of 6 triazole derivatives with FTO protein was investigated. The quenching process of FTO protein induced by six triazole derivatives was static quenching. The hydrophobic force is the main force among which the binding constant of compound 5a and 5f is larger and the compound 5c is the smallest. The results of molecular simulation are in good agreement with the results of spectroscopy.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O657.3;TQ460.1

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