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Purpose <p>Chronic liver disorders are the major causes of morbidity and mortality globally. Despite extensive research, effective therapies remain limited due to complexities of pathophysiology of disease and mainly restricted to alleviation of symptoms rather than identification and treatment of root cause of the disorder. Drug repurposing is a promising strategy to help in rapid identification of new treatments for diseases avoiding R&amp;D failures in early phases of drug development.</p> Methods <p>In present work, we used robust combination of in-silico approaches including pharmacophore modeling, virtual screening, molecular docking, MD simulations and ADMET profiling to screen FDA approved drugs for liver disorders. Employing a developed ligand-based pharmacophore model based on well-studied hepatoprotective phytocompounds, 1615 approved drugs from DrugBank database were screened and filtered.</p> Results <p>Five compounds showed good affinity to the selected liver disease targets, among which drospirenone was found to be the most promising with higher binding affinities to AKT1, TNF, NF-kβ1, mTOR, and INFAR1. The stability of drospirenone in protein complexes was further validated through low RMSD and RMSF vales in the MD simulation studies. The prediction of cytotoxicity revealed promising effect especially for HepG2 liver cancerous cell line. As drospirenone is currently used as an oral contraceptive, it demonstrates well established pharmacokinetic and safety profiles.</p> Conclusion <p>The drug repurposing strategy helped to identify drospirenone as a potential candidate for the treatment of hepatic disorders, thereby accelerating drug discovery process. However, additional in-vitro and in-vivo experiments need to be performed to confirm its effectiveness and safety in clinical practice.</p>

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Computational Repurposing of Approved Drugs: Exploring New Therapeutic Avenues for Liver Disorders

  • 期刊论文

  • 发表日期：

    2025年6月9日

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  • Pranali Jadhav,
  • Asha Thomas,
  • Somdatta Chaudhari,
  • Sohan Chitlange

摘要

Purpose

Chronic liver disorders are the major causes of morbidity and mortality globally. Despite extensive research, effective therapies remain limited due to complexities of pathophysiology of disease and mainly restricted to alleviation of symptoms rather than identification and treatment of root cause of the disorder. Drug repurposing is a promising strategy to help in rapid identification of new treatments for diseases avoiding R&D failures in early phases of drug development.

Methods

In present work, we used robust combination of in-silico approaches including pharmacophore modeling, virtual screening, molecular docking, MD simulations and ADMET profiling to screen FDA approved drugs for liver disorders. Employing a developed ligand-based pharmacophore model based on well-studied hepatoprotective phytocompounds, 1615 approved drugs from DrugBank database were screened and filtered.

Results

Five compounds showed good affinity to the selected liver disease targets, among which drospirenone was found to be the most promising with higher binding affinities to AKT1, TNF, NF-kβ1, mTOR, and INFAR1. The stability of drospirenone in protein complexes was further validated through low RMSD and RMSF vales in the MD simulation studies. The prediction of cytotoxicity revealed promising effect especially for HepG2 liver cancerous cell line. As drospirenone is currently used as an oral contraceptive, it demonstrates well established pharmacokinetic and safety profiles.

Conclusion

The drug repurposing strategy helped to identify drospirenone as a potential candidate for the treatment of hepatic disorders, thereby accelerating drug discovery process. However, additional in-vitro and in-vivo experiments need to be performed to confirm its effectiveness and safety in clinical practice.