Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling

Chem Commun (Camb). 2011 Mar 7;47(9):2517-9. doi: 10.1039/c0cc04937a. Epub 2011 Jan 14.

Abstract

QM/MM modelling of FAAH inactivation by O-biphenyl-3-yl carbamates identifies the deprotonation of Ser241 as the key reaction step, explaining why FAAH is insensitive to the electron-donor effect of conjugated substituents; this may aid design of new inhibitors with improved selectivity and in vivo potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Binding Sites
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Carbamates / chemistry*
  • Carbamates / pharmacology
  • Computer Simulation
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Protons
  • Quantum Theory
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Biphenyl Compounds
  • Carbamates
  • Enzyme Inhibitors
  • Protons
  • cyclohexylcarbamic acid biphenyl-3-yl ester
  • Amidohydrolases
  • fatty-acid amide hydrolase