组合虚拟筛选发现选择性雌激素受体β配体和对硝基苄基酯酶及突变体的分子模拟研究

发布时间：2018-01-21 11:03

本文关键词： 虚拟筛选相似性搜索分子对接同源模建结合自由能　出处：《华东理工大学》2014年硕士论文　论文类型：学位论文

【摘要】：二十世纪八十年代,在新药研究与开发领域出现了一个新颖的药物发现手段——计算机辅助药物设计(computer aided drug design, CADD)。它不仅在药物研发领域发挥举足轻重的作用,还在生物大分子的功能性研究中扮演很重要的角色。本论文运用CADD方法寻找靶向作用于雌激素受体p的配体并研究来自于解淀粉芽孢杆菌的对硝基苄基酯酶的改造。论文的第一章主要对计算机辅助药物设计学科进行了简单的介绍,详述了一些和后面两章实验内容相关的方法。论文的第二章主要是将基于2D分子指纹的相似性方法和基于雌激素受体p分子动力学平均结构的对接方法结合来筛选Enamine化合物数据库,以发现选择性ERβ配体。初步的生物活性数据显示挑选的61个化合物有31个在分子水平上表现出ER活性,其中包括14个激动剂、13个拮抗剂、3个部分激动剂以及1个双效配体。激动剂中对ERβ起作用的有12个,其中5个具有高度的ERβ选择性。论文的第三章主要是结合同源模建与分子对接研究以指导对硝基苄基酯酶的突变实验。建好的模型经过优化后,在拉氏图和Profile-3D打分评价中都得到很好的验证。接着我们对蛋白和底物1-(3,4-亚甲二氧苯基)乙酯进行了结构修改后的对接研究,分析野生型蛋白与底物对接结果为后续突变实验提供指导,最终发现了三个改进的突变体,我们从其结合模式以及MM-GBSA自由能计算结果可以很好地解释突变实验现象。论文的第四章是对本论文工作内容的总结。
[Abstract]:1980s. In the field of new drug research and development, a novel drug discovery method, computer aided aided drug design, has emerged. It not only plays an important role in the field of drug research and development. It also plays an important role in the functional study of biomolecules. In this paper, we use CADD method to find ligand targeting estrogen receptor p and study p-nitrobenzyl ester from Bacillus amylolyticus. Enzyme modification. In the first chapter, a brief introduction to the subject of computer aided drug design (CAD) is given, and some methods related to the experimental contents of the following two chapters are described in detail. In the second chapter, the similarity method based on 2D fingerprint and the docking method based on estrogen receptor p molecular dynamics average structure are combined to screen the Enamine compound database. Preliminary bioactivity data showed that 31 of the 61 selected compounds showed ER activity at molecular level, including 14 agonists and 13 antagonists. Three partial agonists and one bifunctional ligand were used. Among them, 12 of the agonists acted on ER 尾, 5 of which had high ER 尾 selectivity. In the third chapter, the homologous modeling and molecular docking were combined to guide the mutation experiment of p-nitrobenzyl esterase. The model was optimized. It was well verified in Laplace diagram and Profile-3D scoring evaluation. Then we studied the structural modification of the protein and the substrate-1-trimethylene dioxophenyl) ethyl ester. The analysis of the docking results between wild-type proteins and substrates provided guidance for subsequent mutation experiments and found three improved mutants. We can explain the experimental phenomenon of mutation from its binding mode and the results of MM-GBSA free energy calculation. Chapter 4th is a summary of the work of this paper.
【学位授予单位】：华东理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R91-39

【共引文献】