Abstract
Severe COVID-19 cases are often characterised by a hyperinflammatory cytokine storm, which leads to immune dysregulation and increased mortality. Simultaneously, opportunistic fungal infections such as mucormycosis have been increasingly reported, especially in immunocompromised individuals. Triazole antifungals are widely used to treat such infections, but their potential immunomodulatory effects remain underexplored. This study aimed to investigate the off-target potential of commonly used antifungal triazoles itraconazole, ketoconazole, posaconazole and voriconazole against human phosphodiesterase-4 (PDE-4), a key enzyme involved in the regulation of pro-inflammatory cytokine expression. To our knowledge, this is the first study to explicitly propose and computationally validate the dual role of triazole antifungals as both antifungal and immunomodulatory agents. A computational approach comprising molecular docking, molecular dynamics (MD) simulations and quantum chemical analysis was employed to evaluate the interaction of the selected triazoles with PDE-4. Binding affinity and interaction stability were compared with roflumilast, a known PDE-4 inhibitor. Among the tested triazoles, posaconazole exhibited the most favourable binding energy (-44.60 kcal/mol via MM-GBSA), forming stable interactions with key residues in the catalytic site of PDE-4, similar to those observed with roflumilast. MD simulations further confirmed the binding stability of posaconazole, as evidenced by favourable RMSD and hydrogen bonding patterns. Quantum chemical analysis indicated strong electrophilicity and reactivity of posaconazole, supporting its potential PDE-4 inhibitory activity. The findings suggest that certain triazole antifungals, especially posaconazole, may both fight fungal infections and reduce the cytokine storm in severe COVID-19, offering a promising rapid-response therapeutic strategy.