【5.3.3】间接药物设计

November 08, 2018 drug 阅读量：次

Indirect Drug Design：

Indirect drug design - drug design based on structures and activities of inhibitors, not on the structures of the receptors!
The basic molecular structures of the inhibitors must be known.
The active conformation of the compounds must be determined

一、基于配体药效团模型的药物设计

药效基团模型法 Pharmacophore modeling

基于配体的药效基团(ligand-based pharmacophore)

药效基团的获取: Pharmacophore perception

简化方法:最强活性化合物的优势构象

简化方法:刚性药物模板

优点：

缺点：

定量构效关系QSAR —— 揭示一组化合物的生物活性与其分子结构特征之间的相互关系，以数学模型表达和概括出量变规律，以此设计新的化合物

活性 = f (分子或片断性质)

QSAR:

Quantitative Structure Activity Relationships (2D and more recently 3D).
Attempts are made to identify (non)linear relationships that exist between physical and/or chemical properties (logP, hydrophobicity/hydrophilicity, frontier molecular orbitals (HOMO, LUMO), solubility/free energy of hydration, pKa(s), etc.) and activity (inhibition).

数据统计——广泛使用计算机的计算和人工智能

数据统计中广泛使用的计算和人工智能

回归 / 相关	MLR(多元线性回归)，FW(Free-Wilson模型)，FB(Fujita-Ban模型)，ALS (适应最小二乘法)，PLS(偏最小二乘法)。
模式识别 / 分类	PCA(主成分分析)，FA(因子分析)，SIMCA，DA(判别分析)，LLM(线性学习机法)，KNN(K最近邻法)，CA(聚类分析)，ANN(人工神经网络)。

Three-Dimensional Quantitative Structure-Activity Relationships 拟合出药物的理化和三维结构参数与药效的定量关系，以此关系设计新的化合物

CoMFA is a widely-used tool for study of quantitative structure-activity relationships (QSAR) at the 3-D level
3-D QSAR approaches use statistical methods to correlate the variation in biological or chemical activity with information on 3-D structure for a series of compounds

The underlying idea of the CoMFA is that differences in a target property (e.g. biological activity) are often closely related to equivalent changes in the shapes and strengths of the non-covalent interaction fields surrounding the molecules
The CoMFA methodology ultimately allows one to design and predict activities of molecules.