Correlation of inhibitor effects on enzyme activity and thermal stability for the integral membrane protein fatty acid amide hydrolase.
The melting curves of fatty acid amide hydrolase (FAAH) in the presence of 29 reversible inhibitors were measured using a thiol-reactive fluorophore. The thermal stability (T(m)) of the FAAH/inhibitor complex varied significantly depending on the chemical characteristics of the inhibitors, notably variations in the head group. Two separate distributions were observed when T(m) was plotted against K(i). The majority of the inhibitors showed a positive correlation between binding affinity and T(m), however inhibitors with a pyridine carboxylic acid moiety in the head group fell in a distinct and uncorrelated distribution when tail groups were varied.
Slaymaker
Ian M
IM
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bracey
Michael
M
Mileni
Mauro
M
Garfunkle
Joie
J
Cravatt
Benjamin F
BF
Boger
Dale L
DL
Stevens
Raymond C
RC
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D008565:Membrane Proteins / Q000378:metabolism; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D008565:Membrane Proteins; D010080:Oxazoles; D011725:Pyridines; D000099252:Fatty Acid Amide Hydrolases