物理化学学报 >> 2004, Vol. 20 >> Issue (05): 512-517.doi: 10.3866/PKU.WHXB20040514

研究论文 上一篇    下一篇

从药物的三维分子结构预测人体小肠吸收

胡桂香;邹建卫;蒋勇军;王艳花;俞庆森   

  1. 浙江大学,宁波理工学院分子设计与营养工程市重点实验室,宁波 315104
  • 收稿日期:2003-10-17 修回日期:2004-01-09 发布日期:2004-05-15
  • 通讯作者: 胡桂香 E-mail:hugx@nit.net.cn

Predicting Human Intestinal Absorption from Threedimensional Molecular Structure of Drugs

Hu Gui-Xiang;Zou Jian-Wei;Jiang Yong-Jun;Wang Yan-Hua;Yu Qing-Sen   

  1. Key Laboratory for Molecular Design and Nutrition Engineering of Ningbo City, Ningbo Institute of Technology, Zhejiang University, Ningbo 315104
  • Received:2003-10-17 Revised:2004-01-09 Published:2004-05-15
  • Contact: Hu Gui-Xiang E-mail:hugx@nit.net.cn

摘要: 在口服药物的发展过程中,人体小肠吸收的预测是候选药物设计、优化和选择的一个主要目标.VolSurf/GRID计算方法作为一个新的工具被用来预测被测化合物的人体小肠吸收,以及测定人体小肠吸收所必需的重要的分子特征.被测化合物包括112个结构不同的类似药物的化合物.使用偏最小二乘判别分析方法在实验数据和人体小肠吸收的理论分子特征之间建立相关性.建立的两个模型之间具有较高的一致性.小肠吸收实验数据与分子特征之间好的相关性(r2=0.82, q2=0.67)表明,从化合物的三维分子结构能够预测人体小肠吸收.有利于人体小肠吸收的药物分子特征包括,分子量中心与亲水区重心的不平衡性,较大的疏水区域以及分子内较少的氢键给体.

关键词: 人体小肠吸收(HIA), 三维, VolSurf, 主成分分析(PCA), 偏最小二乘法(PLS)

Abstract: The prediction of human intestinal absorption is a major goal in the design, optimization, and selection of candidates for the development of oral drugs. A computerized method (VolSurf/GRID) was used as a novel tool for predicting human intestinal absorption of test compound, and for determining the critical molecular properties needed for human intestinal absorption. The tested molecules consisted of 112 diverse drug-like compounds. Partial least squares discriminant analysis was used to correlate the experimental data with the theoretical molecular properties of human intestinal absorption. There was high consistency between two built models. A good correlation (r2=0.82, q2=0.67) between the molecular properties and the experimental data demonstrated that human intestinal absorption could be predicted from the three-dimensional molecular structure of a compound. Favorable structural properties identified for the potent intestinal absorption drugs included strong imbalance between the center of mass of a molecule and the barycenter of its hydrophilic and hydrophobic regions and a definitive hydrophobic region as well as less hydrogen bond donors on the molecule.

Key words: Human intestinal absorption (HIA), Three-dimension, VolSurf, Principal component analysis (PCA), Partial least squares (PLS)