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X-ray crystallographic analysis of alpha-ketoheterocycle inhibitors bound to a humanized variant of fatty acid amide hydrolase

Academic Article
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Overview

related to degree

  • Garfunkle, Joie, Ph.D. in Chemistry, Scripps Research 2004 - 2009

authors

  • Mileni, M.
  • Garfunkle, Joie
  • Ezzili, C.
  • Kimball, F. S.
  • Cravatt, Benjamin
  • Stevens, Raymond
  • Boger, Dale

publication date

  • January 2010

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • Three cocrystal X-ray structures of the alpha-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the alpha-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design.

subject areas

  • Amidohydrolases
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors
  • Models, Molecular
  • Oxazoles
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC2804032

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm9012196

PubMed ID

  • 19924997
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Additional Document Info

start page

  • 230

end page

  • 240

volume

  • 53

issue

  • 1

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