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THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF CYTOCHROMES P450: EFFECT OF INCORPORATING HIGHER-AFFINITY LIGANDS AND POTENTIAL NEW APPLICATIONS

Charles W. Locuson and Jan L. Wahlstrom
Drug Metabolism and Disposition July 2005, 33 (7) 873-878; DOI: https://doi.org/10.1124/dmd.105.004325
Charles W. Locuson
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Abstract

Recently, two new classes of reversible inhibitors, the benzbromarones (BZBRs) and the N-3 substituted phenobarbitals (PBs), were used to study the active site characteristics of CYP2C9 and 2C19, respectively. Since these ligands are some of the first CYP2C ligands to extend into the low nanomolar Ki range (Ki < 100 nM), they were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Given that BZBRs or the PB ligands bind very tightly, it can be assumed that these structures complement the binding pocket(s) for these enzymes. Thus, the resulting models should output a 3D arrangement of interaction sites predicted to be important for near optimal binding to the CYP2C9 and CYP2C19 enzymes. These predicted interaction regions may then improve the ability to predict drug-drug interactions. The resulting models generated from these new high affinity ligands are discussed, as are novel uses of 3D-QSAR and molecular modeling techniques that may be useful in the study of cytochromes P450 specifically.

Footnotes

  • This work was supported by National Institutes of Health Research Grants ES09122 and GM061823.

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

  • doi:10.1124/dmd.105.004325.

  • ABBREVIATIONS: 3D-QSAR, three-dimensional quantitative structure-activity relationship; BZBR, benzbromarone; PB, N-3 substituted phenobarbital/nirvanol.

    • Received February 17, 2005.
    • Accepted April 14, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (7)
Drug Metabolism and Disposition
Vol. 33, Issue 7
1 Jul 2005
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THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF CYTOCHROMES P450: EFFECT OF INCORPORATING HIGHER-AFFINITY LIGANDS AND POTENTIAL NEW APPLICATIONS
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THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF CYTOCHROMES P450: EFFECT OF INCORPORATING HIGHER-AFFINITY LIGANDS AND POTENTIAL NEW APPLICATIONS

Charles W. Locuson and Jan L. Wahlstrom
Drug Metabolism and Disposition July 1, 2005, 33 (7) 873-878; DOI: https://doi.org/10.1124/dmd.105.004325

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THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF CYTOCHROMES P450: EFFECT OF INCORPORATING HIGHER-AFFINITY LIGANDS AND POTENTIAL NEW APPLICATIONS

Charles W. Locuson and Jan L. Wahlstrom
Drug Metabolism and Disposition July 1, 2005, 33 (7) 873-878; DOI: https://doi.org/10.1124/dmd.105.004325
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