Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)
| Autor: | Xiaoshan Min, Stephen T. Thibault, Craig Uyeda, Zhulun Wang, Timothy J. Carlson, Zhihua Ma, Guifen Xu, Darin J. Gustin, Michelle Lindstrom, Frank Kayser, Yihong Li, Nigel Walker, Haoda Xu, Amy Porter |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Oleamide Stereochemistry Amidohydrolases chemistry.chemical_compound Coumarins Tandem Mass Spectrometry Fatty acid amide hydrolase Drug Discovery Hydrolase Catalytic triad Escherichia coli medicine Animals Humans Urea Enzyme Inhibitors Multidisciplinary Molecular Structure biology Drug discovery Active site Anandamide Biological Sciences Rats nervous system Mechanism of action chemistry Biochemistry biology.protein Benzimidazoles Spectrophotometry Ultraviolet lipids (amino acids peptides and proteins) medicine.symptom Crystallization psychological phenomena and processes |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:7379-7384 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1016167108 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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