Desidustat's cardioprotective mechanisms in heart failure: a network pharmacology, molecular docking and dynamics approach.

Heart failure (HF) remains a significant global health issue. Current guideline-directed therapies often focus on neurohormonal modulation and may not fully address the metabolic, oxidative, and inflammatory components central to the disease. Desidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has shown benefits in chronic kidney disease anemia, alongside early evidence of cardiovascular effects in preclinical models. Its complete mechanistic fingerprint in HF is not fully elucidated. This study aimed to generate a robust mechanistic hypothesis by identifying the molecular targets and pathways through which Desidustat may exert cardioprotective effects in HF. An integrated computational approach comprising network pharmacology, molecular docking, and advanced molecular dynamics (MD) simulations was employed. Drug-disease target intersection identified 348 shared targets, which were subjected to topological analysis to pinpoint central hub genes (HSP90AA1, STAT3, ESR1). Molecular docking determined binding affinities to these hubs. The structural stability and binding thermodynamics of the strongest complex (Desidustat-HSP90AA1) were rigorously evaluated using extended MD simulations (up to 200-ns) and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculations. Functional enrichment analysis linked the 348 shared targets to crucial processes in HF, including oxidative stress response, angiogenesis, and the regulation of apoptosis. Topological metrics strongly prioritized HSP90AA1, STAT3, and ESR1 as key regulatory nodes, all of which exhibited favorable binding affinities in docking. The MD simulation confirmed the exceptional structural stability of the Desidustat-HSP90AA1 complex, characterized by consistent low RMSD and a strong binding free energy ΔGbind (Total) of -75.10 ± 5.03 kcal/mol, calculated via MM-GBSA. This hypothesis-generating in silico study suggests that Desidustat acts via a polypharmacological mechanism, potentially modulating key metabolic and inflammatory pathways through central targets like HSP90AA1. These findings provide a mechanistic basis that warrants further experimental and preclinical investigation to evaluate Desidustat's non-hemodynamic cardioprotective potential as a complementary strategy in HF treatment.