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摘要融合蛋白（ABL），它是一种能够不断激活酪氨酸激酶的一种致活酶，然而苯并噻唑可以成为很好的ABL抑制剂。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）对一系列新型苯并噻唑类似物的结构参数和pIC50值进行分析，以42个分子结构和pIC50值已知的苯并噻唑类似物为训练集, 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个新型苯并噻唑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。34710
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此外，本文基于一系列已知化学结构的苯并噻唑类似物，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,进行计算。
毕业论文关键词：三文定量构效关系（3D-QSAR）；苯并噻唑类似物；pIC50值；CoMFA；CoMSIA
Design of Benzothiazole analogue for restraining Wild type and T135I and breakpoint cluster region-ablelson
Abstract
Fusion protein (ABL), it is a capable of continuous activation of tyrosine kinase A induced enzyme activity. However, benzene and thiazole analogs can become very good ABL inhibitors.
This paper uses comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of a series of novel benzothiazole analogues of the structure parameters and pIC50 value were analyzed, with 64 molecular structure and pIC50 value of the known benzothiazole analogues for the training set, with three-dimensional quantitative structure-activity the relationship between (3D-QSAR) method for predicting model is established, using a method of extraction (leave one out, LOO) to test the credibility of prediction model, followed by a model consisting of 12 benzothiazole analogues of the test set to validate model predictive ability, using cross validation coefficient Q2 and the correlation coefficient of R2 to confirm whether 3D-QSAR value prediction model has a good predictive ability. From the results of potential map analysis of CoMSIA and CoMFA, a series of new compounds were designed, and the compounds were found to have higher inhibitory activity.. The results show that the 3D-QSAR model is clearly and well predicted by statistics..
In addition, in this paper, a series of known chemical structure of benzothiazole based analogue, establishes the three-dimensional pharmacophore model. The best model of the model was selected, and the reliability of the model was verified by the test set and Fischer random verification method..
Key words：Three-dimensional quantitative structure-activity relationship (3D-QSAR);new Benzothiazole 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 1
1.3 主要研究内容 3
第二章 理论原理及计算方法 5
2.1 SYBYL软件简介 5
2.2 三文定量构效关系（3D-QSAR）的介绍及其基本原理 5
2.3 研究方法概述 6
2.3.1 化合物活性构象的确定 6
2.3.2 分子叠合 6
2.3.3 CoMFA和CoMSIA简介 6
2.4 研究方案 7
2.4.1 数据集的收集 7
2.4.2 模型构建的准备工作及分子叠合，建立training(训练集)，test(测试集) 8
2.4.3 CoMFA模型的建立 8
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