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摘要Combretastatin A-4 结构简单，是一种有效的微管靶向剂，它的抗肿瘤活性来自对细胞有丝分裂的高抑制活性，同时对秋水仙碱促进的微管聚合有竞争性抑制作用。
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本文运用比较分子力场分析方法（CoMFA）和比较分子相似性指数分析法（CoMSIA）对一系列新型五元杂环类Combretastatin A-4 类似物的结构参数和pIC50值进行分析，以64个分子结构和pIC50值已知的Combretastatin A-4 类似物为训练集, 用三文定量构效关系（3D-QSAR）方法建立了预测模型，采用抽一法(leave one out，LOO) 检验了预测模型的可信性，接着用一个由12个新型五元杂环类Combretastatin A-4 类似物组成的测试集进一步验证预测模型的预测能力，用交叉验证系数q2和相关系数R2的值来证实3D-QSAR 预测模型是否有良好的预测能力。通过从CoMFA、CoMSIA等势图的分析结果，设计了一系列新的化合物，发现了从理论上可以得到有更高抑制活性的化合物。研究结果表明我所建立的3D-QSAR模型在统计学上具有明确、良好的预测能力。
此外，本文基于一系列已知化学结构的Combretastatin A-4 类似物，构建了其三文药效团模型。挑选出构效关系最好的药效团模型,通过测试集和Fischer随机验证法检验了该模型的可靠性。24287
毕业论文关键词：三文定量构效关系（3D-QSAR）；新型五元杂环类Combretastatin A-4 类似物；pIC50值；CoMFA；CoMSIA
3D-QSAR studies and design of new five-membered heterocyclic Combretastatin A-4 analogs
Abstract
CA-4 has the advantages of simple structure,its antitumor activity from a high inhibitory activity on the cell mitosis, and promote microtubule polymerization ofcolchicine had a competitive inhibition.
In this paper, using the comparative molecular field analysis (CoMFA) andcomparative molecular similarity indices analysis (CoMSIA) of a series of new fivemembered heterocyclic Combretastatin analogs of A-4 structure parameters and pIC50 value were analyzed, with 64 molecular structure and the value of pIC50Combretastatin A-4 analogs of known as the training set, using three-dimensional quantitative the structure-activity relationship (3D-QSAR) method for predicting model is established, using a method (leave one out, LOO) to test the credibility of prediction model, and then use a consists of 12 novel five membered heterocyclic Combretastatin A-4 analogues of the test set to verify the predictionmodel, using cross validation coefficient Q2 and the correlation coefficient R2value to confirm the 3D-QSAR prediction model have good predictive ability. Theanalysis results from CoMFA, CoMSIA and other potential diagram, a series of new compounds were designed, found theoretically may have higher inhibitoryactivity of compounds. The results show that the 3D-QSAR model I have built the forecast ability of clear, good in the statistics.
In addition, the Combretastatin A-4 analogues of a series of known chemicalstructure based on, constructs the 3D pharmacophore model. Pick out the bestpharmacophore effect relationship model, test the reliability of the model through the test set and Fischer random verification method.
Key words：Three-dimensional quantitative structure-activity relationship (3D-QSAR);new five-membered heterocyclic Combretastatin A-4 analogs;pIC50 value;CoMFA;CoMSIA
目录
第一章 绪论 1
1.1 研究的背景与目的 1
1.2 研究现状和进展 2
1.2.1 增加水溶性 2
1.2.2 A环的结构修饰 2
1.2.3 B环的结构修饰 3
1.2.4 双键的结构修饰 3
1.2.5 COMBRETASTATIN A-4类似物的3D-QSAR 研究进展 4
1.3 主要研究内容 4
1.3.1 分子结构的搭建与优化 4
1.3.2 分子的叠合及建立模型、回归分析以及模型分析 4