title: Distinctive molecular inhibition mechanisms for selective inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.
abstract: 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.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Tu
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Stefania
authors.initials: S
authors.lastname: Ursu
authors.forename: Athena
authors.initials: A
authors.lastname: Sudom
authors.forename: Xuelei
authors.initials: X
authors.lastname: Yan
authors.forename: Haoda
authors.initials: H
authors.lastname: Xu
authors.forename: David
authors.initials: D
authors.lastname: Meininger
authors.forename: Michael
authors.initials: M
authors.lastname: Degraffenreid
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.forename: Marc
authors.initials: M
authors.lastname: Labelle
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Bei
authors.initials: B
authors.lastname: Shan
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D014230:Triazoles; D009249:NADP; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1