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Research ArticleArticle

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Sean Ekins, Dayna C. Mankowski, Dennis J. Hoover, Michael P. Lawton, Judith L. Treadway and H. James Harwood Jr.
Drug Metabolism and Disposition March 2007, 35 (3) 493-500; DOI: https://doi.org/10.1124/dmd.106.013888
Sean Ekins
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Dayna C. Mankowski
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Dennis J. Hoover
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Michael P. Lawton
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Judith L. Treadway
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H. James Harwood Jr.
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This article has a correction. Please see:

  • CORRECTION TO “THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF HUMAN CYP51 INHIBITORS” - July 01, 2007

Abstract

CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14α-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC50 values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC50 of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 μM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius2 receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining.

Footnotes

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

  • doi:10.1124/dmd.106.013888.

  • ABBREVIATIONS: P450, cytochrome P450; QSAR, quantitative structure-activity relationship; 3D, three-dimensional.

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

  • ↵1 Current affiliation: ACT LLC, Jenkintown, Pennsylvania.

  • ↵2 Current affiliation: Department of Pharmacology, University of Connecticut Health Center, Farmington, Connecticut.

    • Received November 13, 2006.
    • Accepted December 26, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (3)
Drug Metabolism and Disposition
Vol. 35, Issue 3
1 Mar 2007
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Research ArticleArticle

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Sean Ekins, Dayna C. Mankowski, Dennis J. Hoover, Michael P. Lawton, Judith L. Treadway and H. James Harwood
Drug Metabolism and Disposition March 1, 2007, 35 (3) 493-500; DOI: https://doi.org/10.1124/dmd.106.013888

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Research ArticleArticle

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Sean Ekins, Dayna C. Mankowski, Dennis J. Hoover, Michael P. Lawton, Judith L. Treadway and H. James Harwood
Drug Metabolism and Disposition March 1, 2007, 35 (3) 493-500; DOI: https://doi.org/10.1124/dmd.106.013888
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