Elucidation of fatty acid amide hydrolase inhibition by potent alpha-ketoheterocycle derivatives from Monte Carlo simulations.
Fatty acid amide hydrolase (FAAH) is a serine hydrolase responsible for the degradation of anandamide, an endogenous cannabinoid agonist, and oleamide, a sleep-inducing lipid. Recently, Boger and co-workers reported a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of 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 through computational analysis of FAAH inhibition using Monte Carlo (MC) simulations in conjunction with free energy perturbation (FEP) calculations. The MC/FEP simulations demonstrate that incorporation of pyridine at the C5 position of the 2-keto-oxazole and 2-keto-1,3,4-oxadiazole derivatives significantly enhances binding affinity by formation of a hydrogen-bonded array between the pyridyl nitrogen and Lys142 and Thr236. The results also attribute the activity boost upon substitution of oxazole by oxadiazole to reduced steric interactions in the active site and a lower torsional energy penalty upon binding.
Guimarães
Cristiano Ruch Werneck
CR
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, USA.
Boger
Dale L
DL
Jorgensen
William L
WL
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009010:Monte Carlo Method; D011485:Protein Binding; D013816:Thermodynamics; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D006571:Heterocyclic Compounds; D000099252:Fatty Acid Amide Hydrolases