Quantum Mechanics/Molecular Mechanics Modeling of Fatty Acid Amide Hydrolase Reactivation Distinguishes Substrate from Irreversible Covalent Inhibitors

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• 作者：Alessio Lodola ; Luigi Capoferri ; Silvia Rivara ; Giorgio Tarzia ; Daniele Piomelli ; Adrian Mulholland ; Marco Mor
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2500-2512
• 全文大小：618K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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.