Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling

  • Chem Commun (Camb). 2008 Jan 14:(2):214-6. doi: 10.1039/b714136j.
Alessio Lodola  1 ,  Marco Mor ,  Silvia Rivara ,  Christo Christov ,  Giorgio Tarzia ,  Daniele Piomelli ,  Adrian J Mulholland
Affiliations
  • 1. Dipartimento Farmaceutico, Università degli Studi di Parma, 43100, Parma, Italy. [email protected]
PMID: 18092091 DOI: 10.1039/b714136j
Abstract

Modelling of the mechanism of covalent adduct formation by the inhibitor O-arylcarbamate URB524 in FAAH shows that only one of the two possible inhibitor binding orientations is consistent with the experimentally observed irreversible carbamoylation of the nucleophile serine: this is a potentially crucial insight for designing new covalent inhibitors of this promising drug target.

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