X-ray Crystallographic Analysis of Alpha-ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Nov 21

PMID 19924997

Citations 22

Authors

Mauro Mileni

Joie Garfunkle

Cyrine Ezzili

F Scott Kimball

Benjamin F Cravatt

Raymond C Stevens

Dale L Boger

Affiliations

Soon will be listed here.

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.

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