Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling.
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.
Dipartimento Farmaceutico, Università degli Studi di Parma, Parma, Italy. Alessio.Lodola@unipr.it
Alessio
A
Lodola
Luigi
L
Capoferri
Silvia
S
Rivara
Ewa
E
Chudyk
Jitnapa
J
Sirirak
Edyta
E
Dyguda-Kazimierowicz
W
W
Andrzej Sokalski
Mauro
M
Mileni
Giorgio
G
Tarzia
Daniele
D
Piomelli
Marco
M
Mor
Adrian J
AJ
Mulholland
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011522:Protons; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001713:Biphenyl Compounds; D002219:Carbamates; D004791:Enzyme Inhibitors; D011522:Protons; D000099252:Fatty Acid Amide Hydrolases; C475427:cyclohexylcarbamic acid biphenyl-3-yl ester