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Research ArticleArticle

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Abhinav Nath, Michael A. Zientek, Benjamin J. Burke, Ying Jiang and William M. Atkins
Drug Metabolism and Disposition December 2010, 38 (12) 2195-2203; DOI: https://doi.org/10.1124/dmd.110.034645
Abhinav Nath
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Michael A. Zientek
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Benjamin J. Burke
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Ying Jiang
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William M. Atkins
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Abstract

Drug promiscuity (i.e., inhibition of multiple enzymes by a single compound) is increasingly recognized as an important pharmacological consideration in the drug development process. However, systematic studies of functional or physicochemical characteristics that correlate with drug promiscuity are handicapped by the lack of a good way of quantifying promiscuity. In this article, we present a new entropy-based index of drug promiscuity. We apply this index to two high-throughput data sets describing inhibition of cytochrome P450 isoforms by small-molecule drugs and drug candidates, and we demonstrate how drug promiscuity or specificity can be quantified. For these drug-metabolizing enzymes, we find that there is essentially no correlation between a drug's potency and specificity. We also present an index to quantify the susceptibilities of different enzymes to inhibition by diverse substrates. Finally, we use partial least-squares regression to successfully predict isoform specificity and promiscuity of small molecules, using a set of fingerprint-based descriptors.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM-32165] (to W.M.A.); and an American Heart Association Postdoctoral Fellowship (to A.N.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034645.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    DDI
    drug-drug interaction
    PLSR
    partial least-squares regression
    MeCN
    acetonitrile
    DMSO
    dimethyl sulfoxide
    HLM
    human liver microsomes.

  • Received May 21, 2010.
  • Accepted September 14, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Abhinav Nath, Michael A. Zientek, Benjamin J. Burke, Ying Jiang and William M. Atkins
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2195-2203; DOI: https://doi.org/10.1124/dmd.110.034645

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Research ArticleArticle

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Abhinav Nath, Michael A. Zientek, Benjamin J. Burke, Ying Jiang and William M. Atkins
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2195-2203; DOI: https://doi.org/10.1124/dmd.110.034645
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