Predicting caco-2 cell permeation coefficients of organic molecules using membrane-interaction QSAR analysis

被引:97
作者
Kulkarni, A [1 ]
Han, Y [1 ]
Hopfinger, AJ [1 ]
机构
[1] Univ Illinois, Coll Pharm, Lab Mol Modeling & Design, Chicago, IL 60612 USA
来源
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES | 2002年 / 42卷 / 02期
关键词
D O I
10.1021/ci010108d
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A methodology termed membrane-interaction QSAR (MI-QSAR) analysis has been developed in order to predict the behavior of organic compounds interacting with the phopspholipid-rich regions of biological membranes. One important application of MI-QSAR analysis is to estimate ADME properties including the transport of organic solutes through biological membranes as a computational approach to forecasting drug intestinal absorption, A training set of 30 structurally diverse drugs, whose permeability coefficients across the cellular membranes of Caco-2 cells were measured, was used to construct significant MI-QSAR models of Caco-2 cell permeation. Cellular permeation is found to depend primarily upon aqueous solvation free energy (solubility) of the drug, the extent of drug interaction with a model phospholipid (DMPC) monolayer, and the conformational flexibility of the solute within the model membrane. A test set of eight drugs was used to evaluate the predictivity of the MI-QSAR models. The permeation coefficients of the test set compounds were predicted with the same accuracy as the compounds of the training set.
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收藏
页码:331 / 342
页数:12
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