PDB 3QJ9 deposited: 2011-01-28 modified: 2011-05-18
Title Crystal structure of fatty acid amide hydrolase with small molecule inhibitor
Authors Carlson, T.J., Gustin, D.J., Kayser, F., Lindstrom, M., Li, Y., Ma, Z., Min, X., Porter, A.C., Thibault, S.T., Uyeda, C., Walker, N.P., Wang, Z., Xu, G., Xu, H.
Structure factors resolution 2.3 rfactor 0.1782 rfree 0.2208
DPI 0.55 theoretical min: 0.25
Related PDB Entries 3QJ8 3QKV

Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.

Proc.Natl.Acad.Sci.USA 2011 May; 108(18):7379-7384 doi:10.1073/pnas.1016167108

Cross References
Database source Identifier Description
PubMed 21502526 PNASA6
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3QJ9/1 3QJ9 1 dimer 0 2 26 7453