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Research ArticleSymposium Report

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

Eric F. Johnson, J. Patrick Connick, James R. Reed, Wayne L. Backes, Manoj C. Desai, Lianhong Xu, D. Fernando Estrada, Jennifer S. Laurence and Emily E. Scott
Drug Metabolism and Disposition January 2014, 42 (1) 9-22; DOI: https://doi.org/10.1124/dmd.113.054627
Eric F. Johnson
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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J. Patrick Connick
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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James R. Reed
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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Wayne L. Backes
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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Manoj C. Desai
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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Lianhong Xu
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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D. Fernando Estrada
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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Jennifer S. Laurence
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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Emily E. Scott
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California (E.F.J.); Department of Pharmacology and Experimental Therapeutics and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.P.C., J.R.R., W.L.B.); Department of Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California (M.C.D., L.X.); Department of Pharmaceutical Chemistry (J.S.L.) and Department of Medicinal Chemistry (D.F.E., E.E.S.), University of Kansas, Lawrence, Kansas
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Abstract

This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH–cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.

Footnotes

    • Received August 30, 2013.
    • Accepted October 15, 2013.
  • This work was supported in part by the National Institutes of Health [Grants R01 GM031001, F32 GM103069, R01 GM076343, R01 ES004344, and P42 ES013648] and by Gilead Sciences, Inc.

  • This report is a summary of a session at Experimental Biology 2013 sponsored by the Drug Metabolism Division of the American Society for Pharmacology and Experimental Therapeutics.

  • 1 For reviews on boosted protease inhibitors see the following reviews and references therein:

    • 1) Gerber, JG (2000) Using pharmacokinetics to optimize antiretroviral drug-drug interactions in the treatment of human immunodeficiency virus infection Clin Infect Dis 30 Suppl 2:S123-9.

    • 2) Moyle, GJ and Black, D (2001) Principles and practice of HIV-protease inhibitor pharmacoenhancement. HIV Med 2(2):105-13.

    • 3) Cooper CL, van Heeswijk RP, Gallicano K, Cameron DW (2003) A review of low-dose ritonavir in protease inhibitor combination therapy. Clin Infect Dis 36(12):1585-92.

    • 4) Becker SL (2003) The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy. Expert Opin Investig Drugs 12(3):401-12.

    • 5) Gallant JE (2004) Protease-inhibitor boosting in the treatment-experienced patient. AIDS Rev 6(4):226-33.

    • 6) Youle M (2007) Overview of boosted protease inhibitors in treatment-experienced HIV-infected patients. J Antimicrob Chemother 60(6):1195-205.

    • 7) Busse, KH and Penzak, SR (2008) Pharmacological enhancement of protease inhibitors with ritonavir: an update. Expert Review of Clinical Pharmacology 1:533-545.

    • 8) Xu L, Desai MC (2009) Pharmacokinetic enhancers for HIV drugs. Curr Opin Investig Drugs 10(8):775-86.

  • dx.doi.org/10.1124/dmd.113.054627.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (1)
Drug Metabolism and Disposition
Vol. 42, Issue 1
1 Jan 2014
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Research ArticleSymposium Report

Structure/Function of Drug Metabolizing Enzymes

Eric F. Johnson, J. Patrick Connick, James R. Reed, Wayne L. Backes, Manoj C. Desai, Lianhong Xu, D. Fernando Estrada, Jennifer S. Laurence and Emily E. Scott
Drug Metabolism and Disposition January 1, 2014, 42 (1) 9-22; DOI: https://doi.org/10.1124/dmd.113.054627

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Research ArticleSymposium Report

Structure/Function of Drug Metabolizing Enzymes

Eric F. Johnson, J. Patrick Connick, James R. Reed, Wayne L. Backes, Manoj C. Desai, Lianhong Xu, D. Fernando Estrada, Jennifer S. Laurence and Emily E. Scott
Drug Metabolism and Disposition January 1, 2014, 42 (1) 9-22; DOI: https://doi.org/10.1124/dmd.113.054627
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  • Article
    • Abstract
    • Introduction
    • Cytochrome P450 Structure: Common Themes and Variations on the Theme
    • Physical Interactions among NADPH-Cytochrome P450 Reductase, CYP1A2, and CYP2B4 in the Endoplasmic Reticulum
    • Investigations of Human Cytochrome P450 Enzymes with Solution NMR
    • Novel Pharmacoenhancer Cobicistat: Discovery and Development of a CYP3A Inhibitor
    • Summary
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  • Physiological Regulation of Drug Transport and Metabolism
  • P450 System Protein-Protein and Protein-Lipid Interactions
  • Interindividual Variability in P450s
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