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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

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Abstract

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 (11β-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 11β-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 11β-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 11β-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 11β-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.

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(Source: Zinc15 database)

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(Source: PyMOL and ProteinPlus)

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Abbreviations

ADMET:

Absorption, Distribution, Metabolism, Excretion, and Toxicity

11β-HSD1:

11beta-Hydroxysteroid Dehydrogenase Type 1

CBX:

Carbenoxolone

2D:

Two Dimensional

3D:

Three Dimensional

dt:

Step Size

Elec:

Electrostatic

FDA:

Food and Drug Administration

GC:

Glucocorticoid

HBA:

Number of Hydrogen Bond Acceptors

HbA1c:

Glycated Hemoglobin

HBond:

Hydrogen Bond

HOMA-IR:

Homeostatic Model Assessment for Insulin Resistance

HTN:

Hypertension

IR:

Insulin Resistance

LogP:

Logarithmic Octanol Water Partition Coefficient

MD:

Molecular Dynamics

metS:

Metabolic Syndrome

MM-PBSA:

Molecular Mechanics Poisson–Boltzmann Surface Area.

MW:

Molecular Weight

nats:

Number of Atoms

nrotb:

Number of Rotatable Bonds

ns:

Number of Steps

n violations:

Number of Violations

NCBI:

National Center for Biotechnology Information

NPT:

Constant Number of Atoms, Pressure, and Temperature

NVT:

Constant Number of Atoms, Volume, and Temperature

PDB:

Protein Data Bank

RMSD:

Root Mean Square Deviation

SDF:

Spatial Data File

T2D:

Type 2 Diabetes

TIP3P:

Transferable Intermolecular Potential with 3 Points

TPSA:

Topological Polar Surface Area

Vol:

Volume

VDW:

Van Der Waals

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Acknowledgements

The authors thank Manipal School of Life Sciences, Manipal, Kanachur Institute of Medical Sciences, Mangaluru, and National Institute of Technology, Calicut for the support.

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Authors and Affiliations

  1. Department of Biochemistry, Kanachur Institute of Medical Sciences, 575004, Natekal, Mangaluru, Karnataka, India

    Nayana Devang

  2. Manipal School of Life Sciences, Manipal Academy of Higher Education, 576104, Manipal, Karnataka, India

    Bhavya Banjan

  3. School of Biotechnology, National Institute of Technology Calicut, 673601, Calicut, Kerala, India

    Priya V.K.

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Devang, N., Banjan, B. & V.K., P. 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. J Diabetes Metab Disord 22, 657–672 (2023). https://doi.org/10.1007/s40200-023-01191-8

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