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

ABSTRACT: 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.

SUBMITTER: Sakkiah S

PROVIDER: S-EPMC3344271 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Sakkiah Sugunadevi S Meganathan Chandrasekaran C Sohn Young-Sik YS Namadevan Sundaraganesan S Lee Keun Woo KW

International journal of molecular sciences 20120423 4

11β-Hydroxysteroid dehydrogenase type1 (11βHSD1) regulates the conversion from inactive cortisone to active cortisol. Increased cortisol results in diabetes, hence quelling the activity of 11βHSD1 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 11βHSD1 function. The best hypothesis, Hypo1, which contai ...[more]

PMID: 22606035

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Project description:Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

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

Publications

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

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