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Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH).

Min X, Thibault ST, Porter AC, Gustin DJ, Carlson TJ, Xu H, Lindstrom M, Xu G, Uyeda C, Ma Z, Li Y, Kayser F, Walker NP, Wang Z
Proc Natl Acad Sci U S A 108 7379-84 (2011)
Related entries: 3qj8, 3qkv

Cited: 28 times
EuropePMC logo PMID: 21502526

Abstract

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.

Articles - 3qj9 mentioned but not cited (5)

  1. Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH). Min X, Thibault ST, Porter AC, Gustin DJ, Carlson TJ, Xu H, Lindstrom M, Xu G, Uyeda C, Ma Z, Li Y, Kayser F, Walker NP, Wang Z. Proc. Natl. Acad. Sci. U.S.A. 108 7379-7384 (2011)
  2. A Polyphenols-Rich Extract from Moricandia sinaica Boiss. Exhibits Analgesic, Anti-Inflammatory and Antipyretic Activities In Vivo. El-Mekkawy S, Shahat AA, Alqahtani AS, Alsaid MS, Abdelfattah MAO, Ullah R, Emam M, Yasri A, Sobeh M. Molecules 25 E5049 (2020)
  3. Structural analysis of a plant fatty acid amide hydrolase provides insights into the evolutionary diversity of bioactive acylethanolamides. Aziz M, Wang X, Tripathi A, Bankaitis VA, Chapman KD. J Biol Chem 294 7419-7432 (2019)
  4. N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors. Sunduru N, Svensson M, Cipriano M, Marwaha S, Andersson CD, Svensson R, Fowler CJ, Elofsson M. J Enzyme Inhib Med Chem 32 513-521 (2017)
  5. Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing. Zanfirescu A, Nitulescu G, Mihai DP, Nitulescu GM. Pharmaceuticals (Basel) 15 38 (2021)


Reviews citing this publication (3)

  1. The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH). Otrubova K, Ezzili C, Boger DL. Bioorg. Med. Chem. Lett. 21 4674-4685 (2011)
  2. Fatty acid amide hydrolase inhibitors: a patent review (2009-2014). Lodola A, Castelli R, Mor M, Rivara S. Expert Opin Ther Pat 25 1247-1266 (2015)
  3. Computational insights into function and inhibition of fatty acid amide hydrolase. Palermo G, Rothlisberger U, Cavalli A, De Vivo M. Eur J Med Chem 91 15-26 (2015)

Articles citing this publication (20)

  1. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Elmes MW, Kaczocha M, Berger WT, Leung K, Ralph BP, Wang L, Sweeney JM, Miyauchi JT, Tsirka SE, Ojima I, Deutsch DG. J. Biol. Chem. 290 8711-8721 (2015)
  2. A binding site for nonsteroidal anti-inflammatory drugs in fatty acid amide hydrolase. Bertolacci L, Romeo E, Veronesi M, Magotti P, Albani C, Dionisi M, Lambruschini C, Scarpelli R, Cavalli A, De Vivo M, Piomelli D, Garau G. J. Am. Chem. Soc. 135 22-25 (2013)
  3. The synthesis and in vivo evaluation of [18F]PF-9811: a novel PET ligand for imaging brain fatty acid amide hydrolase (FAAH). Skaddan MB, Zhang L, Johnson DS, Zhu A, Zasadny KR, Coelho RV, Kuszpit K, Currier G, Fan KH, Beck EM, Chen L, Drozda SE, Balan G, Niphakis M, Cravatt BF, Ahn K, Bocan T, Villalobos A. Nucl. Med. Biol. 39 1058-1067 (2012)
  4. Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: modulation at the N-portion and distal phenyl ring. Ortar G, Morera E, De Petrocellis L, Ligresti A, Schiano Moriello A, Morera L, Nalli M, Ragno R, Pirolli A, Di Marzo V. Eur J Med Chem 63 118-132 (2013)
  5. Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: steric effects of N-alkyl chain on rat plasma and liver stability. Vacondio F, Silva C, Lodola A, Carmi C, Rivara S, Duranti A, Tontini A, Sanchini S, Clapper JR, Piomelli D, Tarzia G, Mor M. Eur J Med Chem 46 4466-4473 (2011)
  6. Heteroaryl urea inhibitors of fatty acid amide hydrolase: structure-mutagenicity relationships for arylamine metabolites. Tichenor MS, Keith JM, Jones WM, Pierce JM, Merit J, Hawryluk N, Seierstad M, Palmer JA, Webb M, Karbarz MJ, Wilson SJ, Wennerholm ML, Woestenborghs F, Beerens D, Luo L, Brown SM, Boeck MD, Chaplan SR, Breitenbucher JG. Bioorg. Med. Chem. Lett. 22 7357-7362 (2012)
  7. Design, synthesis, and characterization of α-ketoheterocycles that additionally target the cytosolic port Cys269 of fatty acid amide hydrolase. Otrubova K, Cravatt BF, Boger DL. J. Med. Chem. 57 1079-1089 (2014)
  8. Approximating protein flexibility through dynamic pharmacophore models: application to fatty acid amide hydrolase (FAAH). Bowman AL, Makriyannis A. J Chem Inf Model 51 3247-3253 (2011)
  9. Computational proteome-wide screening predicts neurotoxic drug-protein interactome for the investigational analgesic BIA 10-2474. Molinski SV, Shahani VM, MacKinnon SS, Morayniss LD, Laforet M, Woollard G, Kurji N, Sanchez CG, Wodak SJ, Windemuth A. Biochem. Biophys. Res. Commun. 483 502-508 (2017)
  10. Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets. Palermo G, Bauer I, Campomanes P, Cavalli A, Armirotti A, Girotto S, Rothlisberger U, De Vivo M. PLoS Comput. Biol. 11 e1004231 (2015)
  11. Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase. De Simone A, Ruda GF, Albani C, Tarozzo G, Bandiera T, Piomelli D, Cavalli A, Bottegoni G. Chem. Commun. (Camb.) 50 4904-4907 (2014)
  12. Kaempferol Facilitated Extinction Learning in Contextual Fear Conditioned Rats via Inhibition of Fatty-Acid Amide Hydrolase. Ahmad H, Rauf K, Zada W, McCarthy M, Abbas G, Anwar F, Shah AJ. Molecules 25 E4683 (2020)
  13. An unprecedented reversible mode of action of β-lactams for the inhibition of human fatty acid amide hydrolase (hFAAH). Feledziak M, Michaux C, Lambert DM, Marchand-Brynaert J. Eur J Med Chem 60 101-111 (2013)
  14. α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: exploration of conformational constraints in the acyl side chain. Duncan KK, Otrubova K, Boger DL. Bioorg. Med. Chem. 22 2763-2770 (2014)
  15. SAR and LC/MS studies of β-lactamic inhibitors of human fatty acid amide hydrolase (hFAAH): evidence of a nonhydrolytic process. Feledziak M, Muccioli GG, Lambert DM, Marchand-Brynaert J. J. Med. Chem. 54 6812-6823 (2011)
  16. (S)-1-(Pent-4'-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): synthesis, biological evaluation and molecular modelling. Caruano J, Feledziak M, Labar G, Michaux C, Perpète EA, Muccioli GG, Robiette R, Marchand-Brynaert J. J Enzyme Inhib Med Chem 29 654-662 (2014)
  17. An endocannabinoid catabolic enzyme FAAH and its paralogs in an early land plant reveal evolutionary and functional relationship with eukaryotic orthologs. Haq I, Kilaru A. Sci Rep 10 3115 (2020)
  18. Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition. Morgillo CM, Lupia A, Deplano A, Pirone L, Fiorillo B, Pedone E, Luque FJ, Onnis V, Moraca F, Catalanotti B. Int J Mol Sci 23 15502 (2022)
  19. Secretion, isotopic labeling and deglycosylation of N-acylethanolamine acid amidase for biophysical studies. Pavlopoulos S, Pelekoudas DN, Benchama O, Rawlins CM, Agar JN, West JM, Malamas M, Zvonok N, Makriyannis A. Protein Expr. Purif. 145 108-117 (2018)
  20. ω-Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase. Dato FM, Sheikh M, Uhl RZ, Schüller AW, Steinkrüger M, Koch P, Neudörfl JM, Gütschow M, Goldfuss B, Pietsch M. ChemMedChem 13 1833-1847 (2018)


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