Discovery of novel inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 using in silico structure-based screening approach for the treatment of type 2 diabetes.

Purpose: The current study is aimed to perform structure-based screening of FDA-approved drugs that can act as novel inhibitor of the 11beta- hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme. Methods: Structural analogs of carbenoxolone (CBX) were selected from DrugBank database and their Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) parameters were investigated by SwissADME. Molecular docking of CBX analogs against 11ß-HSD1 was performed by AutoDock tool, their binding patterns were visualized using PyMOL and the interacting amino acids were determined by ProteinPlus tool. Molecular dynamics simulation was performed on the docked structure of 11ß-HSD1 (Protein Data Bank (PDB) code: 2ILT) using GROMACS 2018.1. Results: The binding energies of hydrocortisone succinate, medroxyprogesterone acetate, testolactone, hydrocortisone cypionate, deoxycorticosterone acetate, and hydrocortisone probutate were lower than that of substrate corticosterone. The molecular dynamics simulation of 11ß-HSD1 and hydrocortisone cypionate docked structure showed that it formed a stable complex with the inhibitor. The Root mean square deviation (RMSD) of the protein (0.37 ± 0.05 nm) and ligand (0.41 ± 0.06 nm) shows the stability of the ligand-protein interaction. Conclusion: The docking study revealed that hydrocortisone cypionate has a higher binding affinity than carbenoxolone and its other analogs. The molecular dynamics simulation indicated the stability of the docked complex of 11ß-HSD1 and hydrocortisone cypionate. These findings indicate the potential use of this FDA approved drug in the treatment of type 2 diabetes. However, validation by in vitro inhibitory studies and clinical trials on type 2 diabetes patients is essential to confirm the current findings.

Pseudokinases: Prospects for expanding the therapeutic targets armamentarium.

Pseudokinases are pseudoenzyme variants of the protein kinase superfamily that primarily signal through non-catalytic mechanisms. The aberrant expression of pseudokinases correlates with the pathogenesis of many human diseases. However, pseudokinases remain relatively untapped as therapeutic targets due to difficulties associated with regulating their biological functions. Many protein kinase- and few pseudokinase-specific inhibitors have been reported to influence the non-catalytic functions of active kinases, giving the hope that pseudokinases can also be exploited for therapeutic purposes. This chapter presents the structural characteristics of selected pseudokinases, their known roles in human diseases, and the progress made toward developing pseudokinase-centric therapies.

Effect of licorice on patients with HSD11B1 gene polymorphisms- a pilot study.

The positive association of HSD11B1 gene polymorphism with type 2 diabetes (T2D) and prediabetic conditions has been revealed. In the current study, we assessed the effectiveness of licorice on the clinical profile of the patients with HSD11B1 gene polymorphism. Licorice (Glycyrrhiza Glabra) is a competitive inhibitor of 11 beta-hydroxysteroid dehydrogenase 1 (11ß-HSD1) enzyme and has been traditionally reported as an anti-ulcer, anti-pyretic, anti-thirst, anti-inflammatory, hypoglycemic and hypolipidemic agent. The aim of the study was to assess the effectiveness of licorice on the clinical profile of participants with HSD11B1 gene polymorphism. The study was performed using diabetic patients with HSD11B1 gene polymorphism. Biochemical and anthropometric parameters were measured using standard diagnostic tools. Fourteen patients were divided into two groups by simple randomization, Licorice group (treated with 750 mg licorice/day for three weeks), and placebo group (treated with 750 mg placebo/day for three weeks). Investigations were repeated at the end of three weeks. Licorice showed a significant reduction in serum insulin levels (p = 0.03). There was no significant change in any other clinical parameters either by licorice or placebo. Conclusively, licorice moderately improves serum insulin levels in patients with HSD11B1 gene polymorphism. From our pilot study, the safety of licorice is confirmed at a dose of 750 mg/day. However, the study can be repeated at a higher dose to show its effectiveness and safety.

Association of HSD11B1 gene polymorphisms with type 2 diabetes and metabolic syndrome in South Indian population.

BACKGROUND: 11beta-hydroxysteroid dehydrogenase Type 1 (11ß-HSD1) is an NADP or NADPH-dependent enzyme that generates cortisol from cortisone for a local glucocorticoid action. Functional polymorphisms within 11beta-hydroxysteroid dehydrogenase Type 1 (HSD11B1) gene have shown an association with various factors, including insulin resistance (IR) and hypertension. In our study, we have assessed the association of HSD11B1 (rs12086634 and rs846910) gene polymorphisms with type 2 diabetes (T2D) and metabolic syndrome (metS). METHODS: In the present study, 616 subjects were enrolled. DNA from T2D subjects (n=207), metS subjects (n=101), and their age and sex matched control subjects were analyzed. Genotyping of HSD11B1 rs12086634 and rs846910 single nucleotide polymorphisms was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR). An odds ratio and 95% confidence interval were calculated to determine the association of HSD11B1 gene polymorphisms with T2D and metS. RESULTS: The association analysis indicated that HSD11B1 rs12086634 TG contributed to an increased risk of both T2D (OR=1.91; 95% CI-1.33-2.76, P=0.0005) and metS (OR=2.37; 95% CI-1.39-4.05, P=0.0015), but HSD11B1 rs846910 AG contributed to an increased risk of T2D (OR=1.62; 95% CI-1.02-2.57, P=0.03) only. There was a statistically significant difference in systolic blood pressure between the control group with HSD11B1 rs12086634 TG genotype (128.96±13.19mmHg) and the control group with HSD11B1 rs12086634 TT genotype (123.27±10.84mmHg). CONCLUSIONS: The results of our study indicated that the HSD11B1 rs12086634 is associated with both T2D and metS, but HSD11B1 rs846910 is associated with only T2D in South Indian population.