Repurposing Perindopril: A Docking-Based Investigation Targeting IL-6 and IL-8

Abstract

Introduction: Perindopril is a widely used angiotensin-converting enzyme (ACE) inhibitor known for its cardiovascular protective effects. Emerging evidence suggests that ACE inhibitors may also exert anti-inflammatory and tissue-protective actions by modulating inflammatory mediators. Pro-inflammatory cytokines such as Interleukin-6 (IL-6) and Interleukin-8 (IL-8) play a critical role in chronic inflammation, angiogenesis, and tumor progression, particularly in hepatocellular carcinoma (HCC) induced by dimethyl nitrosamine (DMN).

Objectives: The present study aimed to evaluate the binding affinity and interaction profile of Perindopril with IL-6 and IL-8 using molecular docking analysis to explore its potential role in cytokine modulation and to establish a computational basis for its antiproliferative effect in DMN-induced HCC.

Methods: The three-dimensional structures of IL-6 and IL-8 were retrieved from the Protein Data Bank. Perindopril structure was obtained from PubChem and prepared for docking. Molecular docking was performed using AutoDock Vina after appropriate protein and ligand preparation. Active site identification, grid generation, and docking simulations were carried out. Interaction analysis was performed using Discovery Studio Visualizer and PyMOL to evaluate hydrogen bond and hydrophobic interactions.

Results: Perindopril demonstrated favorable binding affinity with IL-6 and IL-8, with docking scores of −4.49 kcal/mol and −4.58 kcal/mol, respectively. The ligand formed multiple conventional hydrogen bonds and hydrophobic alkyl interactions with key amino acid residues within the active sites of both cytokines, indicating stable protein–ligand complex formation.

Conclusions: The docking findings suggest that Perindopril can interact effectively with major pro-inflammatory cytokines IL-6 and IL-8, providing computational evidence for its potential modulatory role in inflammation-associated carcinogenesis. These results form a mechanistic basis for further in vivo evaluation of the antiproliferative effect of Perindopril in DMN-induced hepatocellular carcinoma.