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On-column ligand exchange for structure-based drug design: a case study with human 11?-hydroxysteroid dehydrogenase type 1.

ABSTRACT: Successfully forming ligand-protein complexes with specific compounds can be a significant challenge in supporting structure-based drug design for a given protein target. In this respect, an on-column ligand- and detergent-exchange method was developed to obtain ligand-protein complexes of an adamantane series of compounds with 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) after a variety of other complexation methods had failed. This report describes the on-column exchange method and an unexpected byproduct of the method in which artificial trimers were observed in the structures.

SUBMITTER: Qin W

PROVIDER: S-EPMC3374522 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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On-column ligand exchange for structure-based drug design: a case study with human 11β-hydroxysteroid dehydrogenase type 1.

Qin Wenying W Judge Russell A RA Longenecker Kenton L KL Solomon Larry R LR Harlan John E JE

Acta crystallographica. Section F, Structural biology and crystallization communications 20120421 Pt 5

Successfully forming ligand-protein complexes with specific compounds can be a significant challenge in supporting structure-based drug design for a given protein target. In this respect, an on-column ligand- and detergent-exchange method was developed to obtain ligand-protein complexes of an adamantane series of compounds with 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) after a variety of other complexation methods had failed. This report describes the on-column exchange method and an un ...[more]

PMID: 22691797

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11?-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects.

Project description:Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11?-HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11?-HSD1 KO mouse skin phenotype. 11?-HSD1 activity was elevated in aged human and mouse skin and in PE compared with donor-matched photo-protected human biopsies. Age-induced dermal atrophy with deranged collagen structural organization was prevented in 11?-HSD1 KO mice, which also exhibited increased collagen density. We found that treatment of HDFs with physiological concentrations of cortisol inhibited rate-limiting steps in collagen biosynthesis and processing. Furthermore, topical 11?-HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11?-HSD1 KO mice. These findings suggest that elevated 11?-HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11?-HSD1 inhibitors may be useful in the treatment of age-associated impairments in dermal integrity and wound healing.

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Crystal structures of 11?-hydroxysteroid dehydrogenase type 1 and their use in drug discovery.

Project description:Cortisol is synthesized by 11?-hydroxysteroid dehydrogenase type 1, inhibitors of which may treat disease associated with excessive cortisol levels. The crystal structures of 11?-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.

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Mouse 11?-hydroxysteroid dehydrogenase type 2 for human application: homology modeling, structural analysis and ligand-receptor interaction.

Project description:Mouse (m) 11?-hydroxysteroid dehydrogenase type 2 (11?HSD2) was homology-modeled, and its structure and ligand-receptor interaction were analyzed. The modeled m11?HSD2 showed significant 3D similarities to the human (h) 11?HSD1 and 2 structures. The contact energy profiles of the m11?HSD2 model were in good agreement with those of the h11?HSD1 and 2 structures. The secondary structure of the m11?HSD2 model exhibited a central 6-stranded all-parallel ?-sheet sandwich-like structure, flanked on both sides by 3-helices. Ramachandran plots revealed that only 1.1% of the amino acid residues were in the disfavored region for m11?HSD2. Further, the molecular surfaces and electrostatic analyses of the m11?HSD2 model at the ligand-binding site exhibited that the model was almost identical to the h11?HSD2 model. Furthermore, docking simulation and ligand-receptor interaction analyses revealed the similarity of the ligand-receptor bound conformation between the m11?HSD2 and h11?HSD2 models. These results indicate that the m11?HSD2 model was successfully evaluated and analyzed. To the best of our knowledge, this is the first report of a m11?HSD2 model with detailed analyses, and our data verify that the mouse model can be utilized for application to the human model to target 11?HSD2 for the development of anticancer drugs.

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Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design.

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Inhibition of 11?-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole.

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Formation of threohydrobupropion from bupropion is dependent on 11?-hydroxysteroid dehydrogenase 1.

Project description:Bupropion is widely used for treatment of depression and as a smoking-cessation drug. Despite more than 20 years of therapeutic use, its metabolism is not fully understood. While CYP2B6 is known to form hydroxybupropion, the enzyme(s) generating erythro- and threohydrobupropion have long remained unclear. Previous experiments using microsomal preparations and the nonspecific inhibitor glycyrrhetinic acid suggested a role for 11?-hydroxysteroid dehydrogenase 1 (11?-HSD1) in the formation of both erythro- and threohydrobupropion. 11?-HSD1 catalyzes the conversion of inactive glucocorticoids (cortisone, prednisone) to their active forms (cortisol, prednisolone). Moreover, it accepts several other substrates. Here, we used for the first time recombinant 11?-HSD1 to assess its role in the carbonyl reduction of bupropion. Furthermore, we applied human, rat, and mouse liver microsomes and a selective inhibitor to characterize species-specific differences and to estimate the relative contribution of 11?-HSD1 to bupropion metabolism. The results revealed 11?-HSD1 as the major enzyme responsible for threohydrobupropion formation. The reaction was stereoselective and no erythrohydrobupropion was formed. Human liver microsomes showed 10 and 80 times higher activity than rat and mouse liver microsomes, respectively. The formation of erythrohydrobupropion was not altered in experiments with microsomes from 11?-HSD1-deficient mice or upon incubation with 11?-HSD1 inhibitor, indicating the existence of another carbonyl reductase that generates erythrohydrobupropion. Molecular docking supported the experimental findings and suggested that 11?-HSD1 selectively converts R-bupropion to threohydrobupropion. Enzyme inhibition experiments suggested that exposure to bupropion is not likely to impair 11?-HSD1-dependent glucocorticoid activation but that pharmacological administration of cortisone or prednisone may inhibit 11?-HSD1-dependent bupropion metabolism.

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A urine-concentrating defect in 11?-hydroxysteroid dehydrogenase type 2 null mice.

Project description:In aldosterone target tissues, 11?-hydroxysteroid dehydrogenase type 2 (11?HSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2(-/-) mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2(-/-) mice and controls. Hsd11b2(-/-) mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (?2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport (aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2(-/-) mice (>6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2(-/-) mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2(-/-) mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin.

| S-EPMC3423112 | biostudies-literature

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11?-Hydroxysteroid Dehydrogenase Type 1 (11?-HSD-1).

Project description:Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11?-hydroxysteroid dehydrogenase-type 1 (11?-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11?-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

| S-EPMC4094253 | biostudies-literature

Identification of important chemical features of 11?-hydroxysteroid dehydrogenase type1 inhibitors: application of ligand based virtual screening and density functional theory.

Project description:11?-Hydroxysteroid dehydrogenase type1 (11?HSD1) regulates the conversion from inactive cortisone to active cortisol. Increased cortisol results in diabetes, hence quelling the activity of 11?HSD1 has been thought of as an effective approach for the treatment of diabetes. Quantitative hypotheses were developed and validated to identify the critical chemical features with reliable geometric constraints that contribute to the inhibition of 11?HSD1 function. The best hypothesis, Hypo1, which contains one-HBA; one-Hy-Ali, and two-RA features, was validated using Fischer's randomization method, a test and a decoy set. The well validated, Hypo1, was used as 3D query to perform a virtual screening of three different chemical databases. Compounds selected by Hypo1 in the virtual screening were filtered by applying Lipinski's rule of five, ADMET, and molecular docking. Finally, five hit compounds were selected as virtual novel hit molecules for 11?HSD1 based on their electronic properties calculated by Density functional theory.

| S-EPMC3344271 | biostudies-literature

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