Related Experiment Video
Updated: May 16, 2025
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Exploring disulfiram mechanisms in renal fibrosis: insights from biological data and computational approaches
Vishal S Patil1, Chandragouda R Patil1, Harun M Patel2
1Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India.
Background:
Disulfiram (DSF) is an anti-alcoholic drug that has been reported to inhibit the epithelial-to-mesenchymal transition and crosslinking during fibrosis, pyroptosis, and inflammatory NF-κB and Nrf-2 signaling pathways. However, there is insufficient evidence to support the mechanisms of DSF in preventing renal fibrosis (RF). Therefore, the current study aimed to elucidate the DSF-modulated targets and pathways in renal fibrosis.
Methods:
The common proteins between DSF and RF were screened for protein-protein interaction, pathway enrichment, cluster, and gene ontology analysis. Molecular docking was executed for core genes using AutoDock Vina through the POAP pipeline. Molecular dynamics (MD) simulation (100 ns) was performed to infer protein-ligand stability, and conformational changes were analyzed by free energy landscape (FEL).
Results:
A total of 78 targets were found to be common between DSF and RF, of which NFKB, PIK3CA/R1, MTOR, PTGS2, and MMP9 were the core genes. PI3K-Akt signaling followed by JAK-STAT, TNF, Ras, ErbB, p53, phospholipase D, mTOR, IL-17, NF-κB, AMPK, VEGF, and MAPK signaling pathways were modulated by DSF in RF. DSF showed a direct binding affinity with active site residues of core genes, and except for DSF with NF-κB, all other complexes, including the standard, were found to be stable during 100 ns MD simulation with minimal protein-ligand root mean squared deviation and residual fluctuations and higher compactness with broad conformational changes.
Conclusion:
DSF protects against renal fibrosis, and this study paves the way for experimental investigation to repurpose DSF for treating RF.
Insights
Disulfiram (DSF) drug may treat renal fibrosis by targeting key genes and pathways. This study elucidates DSF's mechanisms, suggesting its repurposing potential for renal fibrosis treatment.
Area of Science:
- Pharmacology
- Nephrology
- Computational Biology
Background:
- Disulfiram (DSF), an anti-alcoholic drug, shows potential in inhibiting fibrosis and inflammatory pathways.
- Evidence for DSF's mechanism in preventing renal fibrosis (RF) is limited.
- This study investigates DSF's targets and pathways in renal fibrosis.
Purpose of the Study:
- To elucidate the molecular targets and signaling pathways modulated by Disulfiram (DSF) in the context of renal fibrosis (RF).
- To identify core genes and protein interactions involved in DSF's effect on RF.
- To explore the potential of repurposing DSF for treating renal fibrosis.
Main Methods:
- Screening of common proteins between DSF and RF.
- Protein-protein interaction, pathway enrichment, and gene ontology analysis.
- Molecular docking and 100 ns molecular dynamics (MD) simulations to assess protein-ligand stability and conformational changes.
Main Results:
- Identified 78 common targets between DSF and RF, with NFKB, PIK3CA/R1, MTOR, PTGS2, and MMP9 as core genes.
- DSF modulates multiple signaling pathways including PI3K-Akt, JAK-STAT, TNF, and NF-κB in RF.
- Molecular docking and MD simulations confirmed stable binding affinity of DSF with core genes, indicating therapeutic potential.
Conclusions:
- Disulfiram (DSF) demonstrates protective effects against renal fibrosis.
- The study provides a mechanistic basis for repurposing DSF in treating renal fibrosis.
- Further experimental validation is warranted to confirm DSF's efficacy in RF treatment.
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