计算机辅助老年痴呆症及流感病毒抑制剂的虚拟筛选与设计

【作者】 郑会勤；

【导师】 魏冬青；

【作者基本信息】 天津师范大学 ， 物理化学， 2007， 硕士

【摘要】 计算机辅助药物设计在新药的研究与发现过程中起着不可忽视的作用，它不仅加快了药物的研究与开发的速度，也节省了大量资金，已经成为药物开发过程中的一种重要手段。全文共分四章，具体内容概括如下：第一章概述计算机辅助药物设计的理论基础及本文研究对象的文献背景。第二章在现代化学信息学和生物信息学的基础上，以现有的治疗老年痴呆症的药物GTS-21为模板分子，在中药化学数据库中寻找新的老年痴呆症的候选药物。计算采用相似性搜索，柔性叠合以及分子对接方法，得到一个与α7受体结合较好的分子Mol7235及二者的合理复合物结构，并进一步分析Mol7235与α7 N-胆碱受体的详细作用情况。这些信息将有助于设计出效果更好的治疗老年痴呆症的药物。第三章采用乙酰胆碱酯酶与石杉碱甲的复合物的晶体结构((PDB code：lvot)，利用相似性搜索和分子对接技术，从中药数据库中筛选出分子Mol3935，得到乙酰胆碱酯酶与Mol3935的最佳复合物结构。根据以上信息，并在一定的理论指导下，对Mol3935进行一系列的合理设计，并得到了较好的设计方案。通过计算结果，分析该中药分子的改造规律。以上信息将有助于设计新的或优化已有的治疗老年痴呆症的乙酰胆碱酯酶抑制剂。第四章基于量子化学和分子力学原理，分别对同一组最为常见神经氨酸酶抑制剂---环己烯类神经氨酸酶抑制剂进行2D-QSAR和3D-QSAR研究，得到了三个2D-QSAR(其中一个最好)模型和一个3D-QSAR模型，结果表明2D-QSAR模型与3D-QSAR模型的预测效果基本上一致，验证了所得模型的可靠性。相比之下，3D-QSAR模型比2D-QSAR模型多出更多的三维结构信息，但2D-QSAR能提供比3D-QSAR更多的物理和化学性质的信息，二者相互结合，取长补短，可指导优化已有的神经氨酸酶抑制剂或设计及合成新的神经氨酸酶抑制剂。更多还原

【Abstract】 Computer-Aided Drug Design(CADD) plays an important role in the discovery of new drugs. It not only makes a rapid progress in the study and discovery new drugs but saves lots of money. CADD has been an important method in new drug discovery. There are four chapters in my thesis research. The detailed contents are as follows:In the first chapter, the knowledges of compute chemistry and the current studies on Alzheimer’s disease and neuraminidase inhibitors are introduced.In the second chapter, based on the cheminformatics and the bioinformatics, a new candidate for Alzheimer’s disease is screened from the Traditional Chinese Medicines Database(TCMD) using GTS-21 as our template molecule. The new found drug candidate for Alzheimer’s disease, Mol 7235, binds with the receptorα7 nAChR better than any other molecules in TCMD. The methods used in my research include similarity search, flexible alignment and molecule docking, The Mol 7235 molecule is different from other molecules as a potential drug candidate and is subject to extensive studies. The results may be very helpful when we modify or design new inhibitors against Alzheimer’s disease.In the third chapter, based on the crystal structure of Acetylcholinestemse complexed with Huperzine A(PDB code: 1 vot), flexible alignment and molecule docking were performed and a new molecule Mol 3935 was screened from TCMD, and the best docking conformation of Acetylcholinestemse complexed with Mol 3935 was obtained. According to the structural information and drug design theories, 38 molecules were designed using rational design method based on the conformation of Mol 3935. Some useful observations were obtained by analysis the results of calculations, which could be helpful to design new inhibitors and refine the old inhibitors of Acetylcholinestemse for Alzheimer’s disease.In the fourth chapter, based on principles of quantum chemistry and molecular mechanics, 2D-QSAR and 3D-QSAR of a set of neuraminidase inhibitors were studied. Three 2D-QSAR models(one is the best among them) and one 3D-QSAR model were obtained. The predictive result showed that 2D-QSAR model is equally effective with the 3D-QSAR model. The 2D-QSAR model provided more information on the chemical and physical properties for drug molecular design than 3D-QSAR did, on the other hand, the 3D-QSAR model provided better molecular structural information for new drug design than 2D-QSAR did. Therefore, the combination model of 2D-QSAR and 3D-QSAR could help us to design and synthesize new neuraminidase inhibitors for influenza.更多还原