ADME evaluation in drug discovery. 7. prediction of oral absorption by correlation and classification

Tingjun Hou, Junmei Wang, Wei Zhang, Xiaojie Xu

Research output: Contribution to journalArticle

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Abstract

A critically evaluated database of human intestinal absorption for 648 chemical compounds is reported in this study, among which 579 are believed to be transported by passive diffusion. The correlation analysis between the intestinal absorption and several important molecular properties demonstrated that no single molecular property could be used as a good discriminator to efficiently distinguish the poorly absorbed compounds from those that are well absorbed. The theoretical correlation models for a training set of 455 compounds were proposed by using the genetic function approximation technique. The best prediction model contains four molecular descriptors: topological polar surface area, the predicted distribution coefficient at pH = 6.5, the number of violations of the Lipinski's rule-of-five, and the square of the number of hydrogenbond donors. The model was able to predict the fractional absorption with an r = 0.84 and a prediction error (absolute mean error) of 11.2% for the training set. Moreover, it achieves an r = 0.90 and a prediction error of 7.8% for a 98-compound test set. The recursive partitioning technique was applied to find the simple hierarchical rules to classify the compounds into poor (%FA ≤ 30%) and good (%FA ≥ 30%) intestinal absorption classes. The high quality of the classification model was validated by the satisfactory predictions on the training set (correctly identifying 95.9% of the compounds in the poor-absorption class and 96.1% of the compounds in the good-absorption class) and on the test set (correctly identifying 100% of the compounds in the poor-absorption class and 96.8% of the compounds in the good-absorption class). We expect that, in the future, the rules for the prediction of carrier-mediated transporting and first pass metabolism can be integrated into the current hierarchical rules, and the classification model may become more powerful in the prediction of intestinal absorption or even human bioavailability. The databases of human intestinal absorption reported here are available for download from the supporting Web site: http:// modem.ucsd.edu/adme.

Original languageEnglish (US)
Pages (from-to)208-218
Number of pages11
JournalJournal of Chemical Information and Modeling
Volume47
Issue number1
DOIs
StatePublished - Jan 2007

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drug
evaluation
Chemical compounds
Discriminators
Modems
Metabolism
Drug Discovery

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Theory and Mathematics
  • Computer Science Applications
  • Information Systems

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ADME evaluation in drug discovery. 7. prediction of oral absorption by correlation and classification. / Hou, Tingjun; Wang, Junmei; Zhang, Wei; Xu, Xiaojie.

In: Journal of Chemical Information and Modeling, Vol. 47, No. 1, 01.2007, p. 208-218.

Research output: Contribution to journalArticle

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abstract = "A critically evaluated database of human intestinal absorption for 648 chemical compounds is reported in this study, among which 579 are believed to be transported by passive diffusion. The correlation analysis between the intestinal absorption and several important molecular properties demonstrated that no single molecular property could be used as a good discriminator to efficiently distinguish the poorly absorbed compounds from those that are well absorbed. The theoretical correlation models for a training set of 455 compounds were proposed by using the genetic function approximation technique. The best prediction model contains four molecular descriptors: topological polar surface area, the predicted distribution coefficient at pH = 6.5, the number of violations of the Lipinski's rule-of-five, and the square of the number of hydrogenbond donors. The model was able to predict the fractional absorption with an r = 0.84 and a prediction error (absolute mean error) of 11.2{\%} for the training set. Moreover, it achieves an r = 0.90 and a prediction error of 7.8{\%} for a 98-compound test set. The recursive partitioning technique was applied to find the simple hierarchical rules to classify the compounds into poor ({\%}FA ≤ 30{\%}) and good ({\%}FA ≥ 30{\%}) intestinal absorption classes. The high quality of the classification model was validated by the satisfactory predictions on the training set (correctly identifying 95.9{\%} of the compounds in the poor-absorption class and 96.1{\%} of the compounds in the good-absorption class) and on the test set (correctly identifying 100{\%} of the compounds in the poor-absorption class and 96.8{\%} of the compounds in the good-absorption class). We expect that, in the future, the rules for the prediction of carrier-mediated transporting and first pass metabolism can be integrated into the current hierarchical rules, and the classification model may become more powerful in the prediction of intestinal absorption or even human bioavailability. The databases of human intestinal absorption reported here are available for download from the supporting Web site: http:// modem.ucsd.edu/adme.",
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