Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling.
Modelling of the mechanism of covalent adduct formation by the inhibitor O-arylcarbamate URB524 in FAAH shows that only one of the two possible inhibitor binding orientations is consistent with the experimentally observed irreversible carbamoylation of the nucleophile serine: this is a potentially crucial insight for designing new covalent inhibitors of this promising drug target.
Lodola
Alessio
A
Dipartimento Farmaceutico, Università degli Studi di Parma, 43100, Parma, Italy. alessio.lodola@unipr.it
Mor
Marco
M
Rivara
Silvia
S
Christov
Christo
C
Tarzia
Giorgio
G
Piomelli
Daniele
D
Mulholland
Adrian J
AJ
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D010100:Oxygen; D012694:Serine; D000099252:Fatty Acid Amide Hydrolases