Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling

Alessio Lodola, Marco Mor, Jitnapa Sirirak, Adrian J. Mulholland*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

29 Citations (Scopus)

Abstract

FAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the carbamoylating compound URB524. These are potentially crucial insights for designing new covalent inhibitors of this drug target.

Original languageEnglish
Pages (from-to)363-367
Number of pages5
JournalBiochemical Society Transactions
Volume37
Issue number2
DOIs
Publication statusPublished - 2009

Keywords

  • Fatty acid amide hydrolase (FAAH)
  • Inhibitor design
  • Quantum mechanics/molecular mechanics (QM/MM)
  • Reaction mechanism
  • Tetrahedral intermediate
  • Transition state

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