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À propos de : Elucidation of Fatty Acid Amide Hydrolase Inhibition byPotent α-Ketoheterocycle Derivatives from Monte CarloSimulations        

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  • Elucidation of Fatty Acid Amide Hydrolase Inhibition byPotent α-Ketoheterocycle Derivatives from Monte CarloSimulations
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  • Fatty acid amide hydrolase (FAAH) is a serine hydrolase responsible for the degradation ofanandamide, an endogenous cannabinoid agonist, and oleamide, a sleep-inducing lipid. Recently, Bogerand co-workers reported a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitorsof FAAH that produce analgesia in animal models (J. Med. Chem.2005, 48, 1849−1856; Bioorg. Med.Chem. Lett.2005, 15, 1423−1428). Key aspects of the structure−activity data are addressed here throughcomputational analysis of FAAH inhibition using Monte Carlo (MC) simulations in conjunction with freeenergy perturbation (FEP) calculations. The MC/FEP simulations demonstrate that incorporation of pyridineat the C5 position of the 2-keto-oxazole and 2-keto-1,3,4-oxadiazole derivatives significantly enhancesbinding affinity by formation of a hydrogen-bonded array between the pyridyl nitrogen and Lys142 andThr236. The results also attribute the activity boost upon substitution of oxazole by oxadiazole to reducedsteric interactions in the active site and a lower torsional energy penalty upon binding.
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