物理化学学报 >> 2006, Vol. 22 >> Issue (04): 486-491.doi: 10.3866/PKU.WHXB20060419

研究论文 上一篇    下一篇

取代基物化参数及其在药物定量构效关系中的应用

周原;梅虎;梁桂兆;李志良   

  1. 重庆大学生物工程教育部与重庆市重点实验室; 重庆大学生物工程学院; 重庆大学化学化工学院, 重庆 400044; 湖南工程学院化学化工系, 湖南 湘潭 411101
  • 收稿日期:2005-07-15 修回日期:2005-12-12 发布日期:2006-04-10
  • 通讯作者: 李志良 E-mail:zlli2662@163.com

Physicochemical Parameters of Substituents and Its Application in Quantitative Structure Activity Relationship for Drugs

ZHOU Yuan;MEI Hu;LIANG Gui-Zhao;LI Zhi-Liang   

  1. Key Laboratory of Biomedical Engineering of Educational Ministry and Chongqing City; College of Biomedical Engineering; College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, P. R. China; Department of Chemistry and Chemical Engineering, Hunan Engineering Institute, Xiangtan 411101, P. R. China
  • Received:2005-07-15 Revised:2005-12-12 Published:2006-04-10
  • Contact: LI, Zhi-Liang E-mail:zlli2662@163.com

摘要: 把取代基电性、立体及疏水性物化参数组合建立一种新取代基描述方法, 对环尿素类和N,N-二甲基-2-溴苯乙胺类衍生物进行结构表征. 对训练样本集通过逐步回归筛选变量, 所建多元线性回归方程R2分别为0.853和0.960, 留一法交互检验Rcv2分别为0.723和0.901;用预测集样本作外部预测, 所得Qext2分别为0.7617和0.7653. 结果显示:环尿素类化合物结构中苯环邻位立体、间位疏水、对位疏水及立体因素对该类药物抗HIV活性产生阻抑作用; N,N-二甲基-2-溴苯乙胺类苯环上取代基立体因素及对位给电子效应有利于提高肾上腺素能阻断活性.

关键词: 环尿素类化合物, N,N-二甲基-2-溴苯乙胺类衍生物, 取代基物化参数, 定量构效关系

Abstract: A novel substituent descriptor based on the 17 different physicochemical parameters about the electronic, hydrophobic and steric properties of substituents is used to describe the chemical structures of 22 cyclic ureas and 22 N,N-dimethyl-2-bromo(substituted phenyl) ethylamine derivatives, respectively. The variables are reduced using stepwise multiple regression (SMR) method for the training set, and the statistical results indicate that the correlation coefficient square for the two series of compounds in the multiple linear regression and cross validation using leave one out (LOO) is 0.853, 0.960, 0.723 and 0.901, respectively. To validate the predictive power of resulting models, external validation are performed for two testing sets with Qext2 values of 0.7617 and 0.7653, respectively. The models obtained also shows that the anti-HIV activity of cyclic ureas is blocked by steric hindrance of ortho and para substituents and hydrophobicity of meta and para substituents, the biological activity of N,N-dimethyl-2-bromo (substituted phenyl) ethylamine derivatives may be improved by introducing the steric substituents and electronic supplying para substituents into phenyl ring.

Key words: Cyclic ureas, N,N-dimethyl-2-bromo(substituted phenyl) ethylamine derivatives, Physicochemical parameters of substituent, Quantitative structure activity relationship (QSAR)