Decoding cytokine interactions for psoriasis therapy through computational repurposing of antihypertensive drugs

Psoriasis is a chronic, immune-mediated skin disorder characterized by excessive inflammation and the overexpression of pro-inflammatory cytokines, including IL-6, IL-1β, IL-17 A, and IFN-γ. Despite the availability of targeted therapies, current treatments often entail high costs, limited accessibility, and adverse side effects. Drug repurposing-utilizing approved medications for novel indications-offers a cost-effective strategy to accelerate the development of alternative therapies with established safety profiles. Twelve FDA-approved antihypertensive drugs-including ACE inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers-were computationally evaluated for anti-inflammatory potential in psoriasis. Target cytokines were identified using network analysis via STRING and Cytoscape. Molecular docking was performed against IL-6, IL-1β, IL-17 A, and IFN-γ. The top-performing ligands underwent further analysis using ADMET prediction, BOILED-Egg visualization, Density Functional Theory (DFT) calculations, and molecular dynamics (MD) simulations to assess pharmacokinetics, electronic properties, and protein-ligand complex stability. Apremilast, a clinically approved anti-psoriatic agent, served as the reference drug. Lisinopril, Ramipril, Amlodipine, and Atenolol emerged as top candidates based on docking scores and pharmacokinetic profiles. Among them, Lisinopril exhibited the strongest binding affinity across all four cytokines, comparable to or exceeding that of Apremilast. Amlodipine demonstrated the highest electronic reactivity, and all selected drugs showed favorable ADMET properties. MD simulations over 200 ns confirmed the dynamic stability of the Lisinopril-IL-6 complex. Lisinopril has shown potential as a molecular candidate through detailed computational analysis of cytokine interactions. However, these results are purely predictions and should be viewed with caution, especially considering reports of potential ACE inhibitor-related psoriasis worsening. Further thorough laboratory, animal, and clinical studies are necessary to assess its practical application and safety in treating psoriasis.