Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling.
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.
Lodola
Alessio
A
Dipartimento Farmaceutico, Università degli Studi di Parma, Parma, Italy.
Mor
Marco
M
Sirirak
Jitnapa
J
Mulholland
Adrian J
AJ
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D002384:Catalysis; D003198:Computer Simulation; D004952:Esters / Q000737:chemistry; D006868:Hydrolysis; D008956:Models, Chemical; D009829:Oleic Acids / Q000737:chemistry; D011789:Quantum Theory; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001713:Biphenyl Compounds; D002219:Carbamates; D004952:Esters; D009829:Oleic Acids; D000099252:Fatty Acid Amide Hydrolases; C475427:cyclohexylcarbamic acid biphenyl-3-yl ester; C029407:oleylamide