PF-3845 Mechanism
Fatty acid amide hydrolase (FAAH) is a dimeric amidase. The FAAH contains a hydrophobic pocket, which is adjacent to the catalytic site and branches into an acyl-chain binding pocket and a membrane access channel. Besides, FAAH also has s second hydrophilic channel, the cytosolic port, which connects the active site to the cytoplasm and interacts with the head groups of FAAH substrates. In addition, FAAH forms a catalytic triad consisting of Ser241, Ser217 and Lys142. [1]
PF-3845 consists of a 3-aminopyridine leaving group and a piperidine moiety. The crystal structure indicates that PF-3845 covalently binds to the catalytic Ser241 in catalytic core of Humanized-rat FAAH (mutant: L192F, F194Y, A377T, S435N, I491V, V495M for human FAAH). Specifically, the piperidyl moieties of PF-3845 bind in a hydrophobic acyl chain-binding pocket, of which, the phenyl aromatic ring of PF-3845 makes a strong aromatic C-H...π interactions with the side chain of Phe192. Furthermore, 4-trifluoromethyl-2-pyridyl group of PF-3845 also forms van der Waals interactions with the hydrophobic residues in acyl chain-binding pocket of FAAH. The interactions result in an improvement in binding affinity between FAAH and PF-3845. [2][3]
References
[1] Bracey MH, et al. Science. 2002, 298(5599), 1793-1796.
[2] Mileni M, et al. J Mol Biol. 2010, 400(4), 743-754.
[3] Ahn K, et al. Chem Biol. 2009, 16(4), 411-420.
