Exploring Disulfiram Mechanisms in Renal Fibrosis: Insights from Biological Data and Computational Approaches

Vishal Patil ¹ Chandragouda R Patil ¹ Harun Patel ¹ Anoop Kumar ^2*

• ¹ R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India
• ² Delhi Pharmaceutical Sciences and Research University, New Delhi, India

Background: Disulfiram (DSF) is an anti-alcoholic drug, that has been reported to inhibit epithelial tomesenchymal transition and crosslinking during fibrosis, pyroptosis, and inflammatory NF-B and Nrf-2 signalling pathway. However, there is insufficient evidence to support the mechanisms of DSF's in the prevention of renal fibrosis (RF). Therefore, the current study aimed to elucidate the DSF-modulated targets and pathways in renal fibrosis.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. MD simulation (100ns) was performed to infer protein-ligand stability and conformational changes were analyzed by free energy landscape (FEL).Results: 78 targets were found 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-B, 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-B, all other complexes including standard 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.DSF protects against renal fibrosis, and this study paves the way for experimental investigation to repurpose DSF for treating RF.