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High-throughput screening of 11beta-hydroxysteroid dehydrogenase type 1 in scintillation proximity assay format
Kelli Solly1, Steven S Mundt, Hratch J Zokian
1Department of Automated Biotechnology, Merck & Co., North Wales, PA, USA.
Abstract:
11beta-Hydroxysteroid dehydrogenase type-1 (11beta-HSD1) is a potential target for the treatment of diabetes, obesity, and hyperlipidemia. This enzyme is mainly responsible for reactivating glucocorticoid hormone inside cells such as adipose cells and liver cells by converting the inactive cortisone to active cortisol. Enzyme assays for 11beta-HSD1 involve either a thin-layer chromatography or high-performance liquid chromatography step to separate cortisol from the substrate cortisone. This additional step is labor intensive and increases the assay time, which limits assay throughput. A homogenous scintillation proximity assay-based method has been recently developed that enables high-throughput screening of 11beta-HSD1 inhibitors. We have applied this novel 11beta-HSD1 assay to screening a large-size compound collection and identified several structural classes of lead compounds that selectively inhibit the activity of 11beta-HSD1.
Insights
Researchers screened compounds to find inhibitors for 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1), an enzyme linked to metabolic diseases. A new high-throughput assay identified promising lead compounds for potential diabetes and obesity treatments.
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1) reactivates glucocorticoids in adipose and liver cells, contributing to metabolic disorders.
- Current enzyme assays for 11beta-HSD1 are labor-intensive and limit screening throughput.
- 11beta-HSD1 is a therapeutic target for diabetes, obesity, and hyperlipidemia.
Purpose of the Study:
- To apply a novel homogenous scintillation proximity assay for high-throughput screening of 11beta-HSD1 inhibitors.
- To identify selective inhibitors of 11beta-HSD1 activity from a large compound collection.
Main Methods:
- Utilized a novel homogenous scintillation proximity assay for 11beta-HSD1.
- Screened a large-size compound collection against the 11beta-HSD1 enzyme.
- Characterized identified lead compounds for selective inhibition.
Main Results:
- Successfully applied the novel assay for high-throughput screening.
- Identified several structural classes of lead compounds.
- These compounds selectively inhibit 11beta-HSD1 activity.
Conclusions:
- The novel scintillation proximity assay is effective for high-throughput screening of 11beta-HSD1 inhibitors.
- Identified lead compounds show potential for developing new treatments for metabolic diseases.
- Selective inhibition of 11beta-HSD1 offers a promising therapeutic strategy.
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