Quantum mechanics/molecular mechanics modeling of fatty acid amide hydrolase reactivation distinguishes substrate from irreversible covalent inhibitors

Alessio Lodola, Luigi Capoferri, Silvia Rivara, Giorgio Tarzia, Daniele Piomelli, Adrian Mulholland*, Marco Mor

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

28 Citations (Scopus)

Abstract

Carbamate and urea derivatives are important classes of fatty acid amide hydrolase (FAAH) inhibitors that carbamoylate the active-site nucleophile Ser241. In the present work, the reactivation mechanism of carbamoylated FAAH is investigated by means of a quantum mechanics/molecular mechanics (QM/MM) approach. The potential energy surfaces for decarbamoylation of FAAH covalent adducts, derived from the O-aryl carbamate URB597 and from the N-piperazinylurea JNJ1661610, were calculated and compared to that for deacylation of FAAH acylated by the substrate oleamide. Calculations show that a carbamic group bound to Ser241 prevents efficient stabilization of transition states of hydrolysis, leading to large increments in the activation barrier. Moreover, the energy barrier for the piperazine carboxylate was significantly lower than that for the cyclohexyl carbamate derived from URB597. This is consistent with experimental data showing slowly reversible FAAH inhibition for the N-piperazinylurea inhibitor and irreversible inhibition for URB597.

Original languageEnglish
Pages (from-to)2500-2512
Number of pages13
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
Publication statusPublished - 28 Mar 2013

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