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Computational identification of potential bioactive compounds from Triphala against alcoholic liver injury by targeting alcohol dehydrogenase

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Abstract

Alcoholic liver injury resulting from excessive alcohol consumption is a significant social concern. Alcohol dehydrogenase (ADH) plays a critical role in the conversion of alcohol to acetaldehyde, leading to tissue damage. The management of alcoholic liver injury encompasses nutritional support and, in severe cases liver transplantation, but potential adverse effects exist, and effective medications are currently unavailable. Natural products with their potential benefits and historical use in traditional medicine emerge as promising alternatives. Triphala, a traditional polyherbal formula demonstrates beneficial effects in addressing diverse health concerns, with a notable impact on treating alcoholic liver damage through enhanced liver metabolism. The present study aims to identify potential active phytocompounds in Triphala targeting ADH to prevent alcoholic liver injury. Screening 119 phytocompounds from the Triphala formulation revealed 62 of them showing binding affinity to the active site of the ADH1B protein. Promising lipid-like molecule from Terminalia bellirica, (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid showed high binding efficiency to a competitive ADH inhibitor, 4-Methylpyrazole. Pharmacokinetic analysis further confirmed the drug-likeness and non-hepatotoxicity of the top-ranked compound. Molecular dynamics simulation and MM–PBSA studies revealed the stability of the docked complexes with minimal fluctuation and consistency of the hydrogen bonds throughout the simulation. Together, computational investigations suggest that (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid from the Triphala formulation holds promise as an ADH inhibitor, suggesting an alternative therapy for alcoholic liver injury.

Graphical abstract

Potential active phytocompounds in Triphala formulation targeting alcohol dehydrogenase to prevent alcoholic liver injury.

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Abbreviations

WHO:

World Health Organization

ADH:

Alcohol dehydrogenase

ADMET:

Absorption, distribution, metabolism, excretion, and toxicity

MD:

Molecular dynamics

MM–PBSA:

Molecular mechanics–Poisson–Boltzmann surface area

PDB:

Protein Data Bank

DS:

Discovery Studio

IMPPAT:

Indian medicinal plants, phytochemistry and therapeutics

CGenFF:

CHARMM general force field

NVT:

Number of particles, volume, and temperature

NPT:

Number of particles, pressure, and temperature

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

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Acknowledgements

We thank the Yenepoya (Deemed to be University) for providing the necessary facility to the Center for Systems Biology and Molecular Medicine (CSBMM) and the Centre for Integrative Omics Data Science (CIODS), to carry out this study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, 575018, India

    Bhavya Banjan & Rajesh Raju

  2. Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, 575018, India

    Thottethodi Subrahmanya Keshava Prasad & Chandran S. Abhinand

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CSA developed the original hypothesis and the computational workflow. CSA and BB conducted molecular docking, ADMET, dynamics studies, and binding-free energy calculations. BB drafted the initial manuscript. CSA, RR, and TSKP critically evaluated the manuscript to ensure the scientific validity of the study. All authors read, edited, and approved the final manuscript.

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Correspondence to Chandran S. Abhinand.

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Banjan, B., Raju, R., Keshava Prasad, T.S. et al. Computational identification of potential bioactive compounds from Triphala against alcoholic liver injury by targeting alcohol dehydrogenase. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10879-9

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