考虑蛋白质柔性的分子对接方法与酰胺联苯醚类FTase抑制剂的构效关系研究
发布时间：2018-11-28 16:59
【摘要】：分子对接方法是基于结构的药物设计的有力工具之一,随着越来越多的蛋白质晶体结构被解析出来,分子对接方法也得到越来越多推广与运用。同时,现有分子对接方法存在的问题也被相继提出来,比如构象搜索不充分、打分函数不够精确、溶剂效应和蛋白质的柔性处理有限等。其中,如何合理处理蛋白质的柔性是分子对接方法研究中难点问题之一。鉴于此,本文以蛋白质与配体小分子结合前后的构象变化尺度为分子柔性尺度评判标准,通过统计分析,对现已解析出晶体结构的蛋白质按照柔性尺度进行聚类,为考虑蛋白质柔性的药物设计提供了数据支持。此外,本文选择部分关键残基柔性的蛋白质作为测试集,对本课题组前期发展的iFitDock和两个主流分子对接方法(AutoDock和Induced-Fit Docking)展开了测试评价,结果表明,iFitDock对配体和蛋白质活性构象的预测精度均显著高于其他分子对接方法,为考虑蛋白质柔性的分子对接方法的发展和完善提供了理论依据。 作为一类重要的翻译后修饰酶,法尼基转移酶(Farnesyltransferase, FTase)对Ras蛋白的膜定位和生物功能的正常运作起着至关重要的作用,是重要的癌症治疗靶标。本课题组在前期的研究中,通过虚拟筛选方法,发现了若干靶向法尼基转移酶的小分子抑制剂。本文针对其中的酰胺联苯醚类抑制剂,采用分子对接方法,对其展开构效关系研究,并依此提出该类化合物的结构修饰策略,结合化学合成及生物测试,获得了一系列高活性的酰胺联苯醚类抑制剂。
[Abstract]:Molecular docking method is one of the powerful tools for structure-based drug design. As more and more protein crystal structures are resolved, molecular docking methods are more and more widely used. At the same time, the existing problems of molecular docking methods have been put forward one after another, such as insufficient conformation search, inaccuracy of scoring function, solvent effect and limited flexibility of protein treatment and so on. Among them, how to deal with the flexibility of protein is one of the difficult problems in molecular docking. In view of this, the conformational change scale before and after the binding of protein with small ligand molecules is taken as the criterion of molecular flexibility scale. Through statistical analysis, the proteins with crystal structure are clustered according to flexible scale. It provides data support for drug design considering protein flexibility. In addition, some flexible proteins of key residues were selected as test sets to test and evaluate iFitDock and two mainstream molecular docking methods (AutoDock and Induced-Fit Docking) developed by our team. The results show that, The prediction accuracy of ligands and protein active conformation by iFitDock is significantly higher than that of other molecular docking methods, which provides a theoretical basis for the development and improvement of molecular docking methods considering protein flexibility. As an important class of post-translational modifiers, farinotransferase (Farnesyltransferase, FTase) plays an important role in the membrane localization and biological function of Ras proteins, and is an important target for cancer therapy. In our previous study, we found some small molecular inhibitors targeting farinyltransferase by virtual screening method. In this paper, the molecular docking method was used to study the unfolded structure-activity relationship of Amidobenzene Ether inhibitors, and the structural modification strategy, chemical synthesis and bioassay of the compounds were proposed. A series of high activity Amidobenzene Ether inhibitors were obtained.
【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
本文编号：2363608
[Abstract]:Molecular docking method is one of the powerful tools for structure-based drug design. As more and more protein crystal structures are resolved, molecular docking methods are more and more widely used. At the same time, the existing problems of molecular docking methods have been put forward one after another, such as insufficient conformation search, inaccuracy of scoring function, solvent effect and limited flexibility of protein treatment and so on. Among them, how to deal with the flexibility of protein is one of the difficult problems in molecular docking. In view of this, the conformational change scale before and after the binding of protein with small ligand molecules is taken as the criterion of molecular flexibility scale. Through statistical analysis, the proteins with crystal structure are clustered according to flexible scale. It provides data support for drug design considering protein flexibility. In addition, some flexible proteins of key residues were selected as test sets to test and evaluate iFitDock and two mainstream molecular docking methods (AutoDock and Induced-Fit Docking) developed by our team. The results show that, The prediction accuracy of ligands and protein active conformation by iFitDock is significantly higher than that of other molecular docking methods, which provides a theoretical basis for the development and improvement of molecular docking methods considering protein flexibility. As an important class of post-translational modifiers, farinotransferase (Farnesyltransferase, FTase) plays an important role in the membrane localization and biological function of Ras proteins, and is an important target for cancer therapy. In our previous study, we found some small molecular inhibitors targeting farinyltransferase by virtual screening method. In this paper, the molecular docking method was used to study the unfolded structure-activity relationship of Amidobenzene Ether inhibitors, and the structural modification strategy, chemical synthesis and bioassay of the compounds were proposed. A series of high activity Amidobenzene Ether inhibitors were obtained.
【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
【参考文献】
相关期刊论文 前1条
1 康玲;李洪林;赵晓宇;王希诚;;一种精细药物分子对接模型和优化方法[J];应用基础与工程科学学报;2008年06期
，本文编号：2363608
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