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摘要：本文采用SYBYL-X程序计算了53苯并咪唑类衍生物的化学结构活性参数。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）和分子对接方法来进行三文定量构效关系和作用机理的理论研究，获得了它们的结构特征、QSAR、作用位点和可能的作用模式。53个苯并咪唑类衍生物被分为两组：其中41个化合物作为训练集，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，12个化合物作为测试集，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。研究结果表明我们所建立的3D-QSAR模型在统计学上具有明确、良好的预测能力。5489
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关键字： 三文定量构效关系（3D-QSAR）；HCV聚合酶抑制剂；2-二取代苯并咪唑-5羧酸；CoMFA ；CoMSIA
3D QSAR studies of benzimidazole derivatives inhibit the hepatitis C virus NS5B
Abstract：Using the SYBYL-X program to calculate the chemical structure-activity parameters of 53 kinds of benzimidazole derivatives. Using the comparative molecular field analysis (CoMFA) index analysis method and comparative molecular similarity (CoMSIA) and molecular docking method for three-dimensional quantitative structure-activity relationship and mechanism of theoretical research, obtained their structure characteristics, QSAR, loci and the possible role model. 53 benzimidazole derivatives were pided into two groups: among 41 compounds as a training set, using three-dimensional quantitative structure-activity relationship (3D-QSAR) method to build a prediction model, using the pumping method (leave one out, LOO) to test the credibility of the forecasting model, and then use a test set by 12 compounds further validate the predictive capability of the prediction model, and using cross-validation coefficient of q2 and the value of the correlation coefficient R2 QSAR prediction model has good predictive ability or not. The results show that the 3D-QSAR model which we built has statistically clear, and good predictive ability. The results show that the 3D-QSAR model which we built has statistically clear, and good predictive ability.
Key words：Three-dimensional quantitative structure-activity relationship (3D-QSAR)；HCV polymerase inhibitors；2-2 instead of benzimidazole - 5 acid；The CoMFA; CoMSIA
目录
1 绪论 5
1.1 研究的背景与目的 5
1.2 研究的历史与现状 6
1.3 主要研究内容 7
1.3.1 分子结构的搭建与优化 7
1.3.2 分子的叠合 7
1.3.3 建立模型、回归分析以及模型分析 8
2 理论原理及计算方法 9
2.1定量构效关系背景 9
2.2 三文定量构效关系的研究方法 9
2.3 SYBYL-X软件简介 10
2.4 研究方法概述 10
2.4.1 化合物活性构象的确定 10
2.4.2 分子叠合 11
2.4.3 CoMFA简介 11
2.4.4 CoMSIA简介 11
2.5 研究方案 11
2.5.1数据搜集 11
2.5.2 建立training(训练集)，test(测试集)及结构的优化 12
2.5.3 建立数据库 12
2.5.4 模型构建的准备工作及分子叠合 12
2.5.5 CoMFA模型的建立 12
2.5.6 CoMSIA模型的建立 13
2.5.7 预测活性计算 13
2.5.8 分子对接 13
3 3D-QSAR的模型结果分析 15