Distinctive molecular inhibition mechanisms for selective inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the NADPH dependent interconversion of inactive cortisone to active cortisol. Excess 11beta-HSD1 or cortisol leads to insulin resistance and metabolic syndrome in animal models and in humans. Inhibiting 11beta-HSD1 activity signifies a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. Herein, we report two highly potent and selective small molecule inhibitors of human 11beta-HSD1. While compound 1, a sulfonamide, functions as a simple substrate competitive inhibitor, compound 2, a triazole, shows the kinetic profile of a mixed inhibitor. Co-crystal structures reveal that both compounds occupy the 11beta-HSD1 catalytic site, but present distinct molecular interactions with the protein. Strikingly, compound 2 interacts much closer to the cofactor NADP+ and likely modifies its binding. Together, the structural and kinetic analyses demonstrate two distinctive molecular inhibition mechanisms, providing valuable information for future inhibitor design.
Tu
Hua
H
Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Powers
Jay P
JP
Liu
Jinsong
J
Ursu
Stefania
S
Sudom
Athena
A
Yan
Xuelei
X
Xu
Haoda
H
Meininger
David
D
Degraffenreid
Michael
M
He
Xiao
X
Jaen
Juan C
JC
Sun
Daqing
D
Labelle
Marc
M
Yamamoto
Hiroshi
H
Shan
Bei
B
Walker
Nigel P C
NP
Wang
Zhulun
Z
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D001681:Biological Assay; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008659:Metabolic Diseases / Q000201:enzymology / Q000473:pathology*; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013449:Sulfonamides; D014230:Triazoles; D009249:NADP; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1