Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid.
Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active 11beta-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11beta-HSD1 and 11beta-HSD2. Here, we compare the biological activity of 18beta-GA and its diastereomer 18alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18alpha-GA selectively inhibits 11beta-HSD1 but not 11beta-HSD2. This is in contrast to 18beta-GA, which preferentially inhibits 11beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11beta-HSD1, we provide an explanation for the differences in the activities of 18alpha-GA and 18beta-GA. This model will be used to design novel selective derivatives of GA.
onepharm Research & Development GmbH, Veterinärplatz 1, Vienna, Austria. Dirk.Classen-Houben@onepharm.com
Dirk
D
Classen-Houben
Daniela
D
Schuster
Thierry
T
Da Cunha
Alex
A
Odermatt
Gerhard
G
Wolber
Ulrich
U
Jordis
Bernhard
B
Kueenburg
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism
C119129:18alpha-glycyrrhetinic acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006034:Glycyrrhetinic Acid