抗结核病药物的3D-QSAR定量结构性质关系研究

抗结核病药物的3D-QSAR定量结构性质关系研究

摘要

采用三维全息原子场作用矢量(3D-HoV AIF)和基于虚拟蛋白质受体原子探针的分子表面随机采样分析(RaSMS)对25个查耳酮类抗结核病药物进行定量构效关系(QSAR)研究。运用多元线性回归(Multiple linear regression, MLR)及偏最小二乘回归(partial least square regression, PLS)建模，同时采用内部及外部双重验证的办法对所得模型稳定性能进行了深入分析和检验。采用3D-HoV AIF 的MLR及PLS建模的复相关系数(R cum2)、留一法(leave-one-out, LOO)交互校验(cross-validation, CV)复相关系数(Q LOO2)和外部样本校验复相关系数(Q ext2)分别为0.984、0.920、0.808和0.998、0.975、0.903；采用RaSMS 分别为0.975、0.914、0.764和0.926、0.905、0.829。结果表明，3D-HoV AIF和RaSMS 都有较好表征抗结核药物分子结构信息，因而能建立具有良好稳定性和预测能力的QSAR模型。

关键词：体外抗菌活性，抗结核病药物，三维全息原子场作用矢量，比较分子/虚拟受体相互作用分析法，定量构效关系

Anti-TB drugs by 3D-QSAR Quantitative Structure-Property

Relationship Study

ABSTRACT

A newly developed three-dimensional holographic vector of atomic interaction field (3D-HoV AIF) and Protein-based virtual surface receptor molecule atom probe analysis of random sampling (RaSMS) were used to describe the chemical structures of 25 Chalcone as antituberculosis agents. Here quantitative structure activity relationship (QSAR) models were built by Multiple linear regression （MLR）and partial least square regression (PLS). The estimation stability and generalization ability of these models were strictly analyzed by both internal and external validations. When use 3D-HoV AIF, the correlation coefficient (R2) of established MLR and PLS，leave-one-out (LOO) cross-validation (CV), predicted values versus experimental ones of external samples were 0.998、0.975、0.903 and 0.926、0.785、0.785, respectively. When use (RaSMS), the results were 0951、0.914、0.829 and 0.928、0.905、0.764. The results indicated that results of PLS here had favorable estimation stability and good prediction capabilities. Satisfactory results showed that 3D-HoV AIF and RaSMS could preferably express information related to biological activity of anti-tuberculosis drug.

KEY WORDS:in vitro antibacterial activity, anti-tuberculosis drug, three-dimensional holographic vector of atomic interaction field, quantitative (3D-HoV AIF), Protein-based virtual surface receptor molecule atom probe analysis of random sampling (RaSMS), structure-activity relationship (QSAR)

目录

摘要 ........................................................................................................................................... I ABSTRACT .............................................................................................................................. II 1 引言 .. (1)

1.1结核病和抗结核病药物简介 (1)

1.1.1 结核病简介 (1)

1.1.2 抗菌活性 (1)

1.1.3 抗结核病药物的发展历史 (1)

1.1.4 抗结合药物回顾 (2)

1.1.5 抗结核新药研究开发的现状 (2)

1.2计量化学简介 (4)

1.3计算机辅助药物分子设计的基本理论与方法 (5)

1.3.1 计算机药物辅助设计的基本理论 (5)

1.3.2 常用的计算机辅助药物设计方法 (5)

1.4定量构效关系研究 (5)

1.4.1 定量构效关系研究的基本理论 (5)

1.4.2 定量构效关系研究的发展 (6)

1.4.3 定量构效关系研究的意义 (7)

1.4.4 定量构效关系的研究现状 (7)

2 原理与方法 (9)

2.1三维全息原子场作用矢量(3D-H O V AIF)的基本概念及相关计算 (9)

2.2基于虚拟蛋白质受体原子探针的分子表面随机采样分析(R A SMS)的基本概念及

相关计算 (15)

2.2.1 蛋白质受体原子探针 (15)

2.2.2 虚拟受体可及表面 (16)

2.2.3 药物分子中常见原子分类 (17)

2.2.4 探针原子与药物配体的作用模式 (17)

2.2.5 RaSMS实现过程 (18)

2.3多元线性回归原理 (19)

2.4偏最小二乘法原理 (20)

3 模型的建立与检验 (22)

3.1数据采集 (22)

3.2变量筛选 (23)

3.3多元线性回归建模 (24)