Crystal Structures of 11β-Hydroxysteroid Dehydrogenase Type 1 and Their Use in Drug Discovery

Abstract

Cortisol is synthesized by 11β-hydroxysteroid dehydrogenase type 1, inhibitors of which may treat disease associated with excessive cortisol levels. The crystal structures of 11β-hydroxysteroid dehydrogenase type 1 that have been released may aid drug discovery. The crystal structures have been analyzed in terms of the interactions between the protein and the ligands. Despite a variety of structurally different inhibitors the crystal structures of the proteins are quite similar. However, the differences are significant for drug discovery. The crystal structures can be of use in drug discovery, but care needs to be taken when selecting structures for use in virtual screening and ligand docking.A significant problem facing society is the increase in obesity. Often observed in obese people is metabolic syndrome, a disease characterized by a variety of symptoms including congestive heart failure, hypertension, atherogenic lipidemia, glucose intolerance, insulin resistance and Type II diabetes [1]. These symptoms, widely recognized as being risk factors for cardio vascular disease [2], are also associated with high levels of the glucocorticoid hormone cortisol [3,4]. Glucocorticoid hormones play essential roles in a range of physiological processes including the regulation of carbohydrate, lipid and bone metabolism, maturation and differentiation of cells, and modulation of inflammatory responses and stress [5][6][7]. They exert their effect primarily through binding to glucocorticoid receptors, leading to altered target gene transcription. Symptoms similar to those of metabolic syndrome are observed in patients suffering from Cushing's syndrome, which is marked by increased glucocorticoid levels [8]. The similarity of these symptoms suggests that the suppression of glucocorticoid activity may be a treatment for the individual indications of metabolic syndrome [9] despite the fact that in metabolic syndrome circulating glucocorticoid levels are not usually elevated [10]. Therefore, it is speculated that intercellular, but particularly intracellular local levels of glucocorticoid regulated by

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…The 11␤-HSD1 structures are similar overall, although the hydrophobic substrate binding pocket, predominantly lined by nonpolar residues and with lower sequence conservation than other regions, shows some variability between species, accounting for the species specificity of inhibitors (32, 626,704). The two subunits of the 11␤-HSD1 homodimer are related by a pseudo-twofold axis.…”

“…Both ends of the substrate binding pocket are open to solvent, allowing ligands that exceed the 12 Å length of the pocket to extend out of it (704). Interactions with Ser170 and Tyr183 stabilize the 11-keto group of the substrate, anchoring it in the active site (331,533).…”

“…704 for a recent review). Of these, three are mouse 11␤-HSD1 (without substrate, with corticosterone bound, and with selective inhibitor bound), three are guinea pig 11␤-HSD1 (one without substrate and two with inhibitor bound), and the remainder are human 11␤-HSD1 with a variety of inhibitors bound, reflecting the strong pharmaceutical interest in 11␤-HSD1 inhibition.…”

16-nor Limonoids from Harrisonia perforata as promising selective 11β-HSD1 inhibitors

“…Despite the structural variety of the different inhibitors that have previously been investigated, the crystal structures of the NADP(H)-dependent 11 β -HSD1 proteins are comparatively similar26. AutoDock 4 was employed to quantify the parameters that are crucial for high affinity ligand binding.…”

Alterations of Cortisol Metabolism in Human Disorders

“…The corresponding human gene for this isozyme, HSD11B1 , is located on chromosome 1 and contains 6 exons with a total length of over 9 kb. Crystal structures of 11-HSD1 are available [5] and have been extensively used for the identification of specific inhibitors of the enzyme [6, 7]. …”