Integrated structure-based and systems-level identification of PDE9A inhibitors for heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a complex and increasingly prevalent cardiovascular disorder with limited effective therapeutic options. Dysregulation of cyclic guanosine monophosphate (cGMP) signaling has been implicated in its pathophysiology. Phosphodiesterase 9A (PDE9A), a cGMP-specific enzyme, has emerged as a potential therapeutic target due to its role in nitric oxide-independent signaling pathways associated with myocardial dysfunction. This study employed an integrated computational framework combining multi-conformational docking, pharmacophore modeling, pharmacophore validation using active–decoy screening, molecular dynamics simulations, and systems-level analyses to identify potential PDE9A inhibitors. Three crystal structures of PDE9A (4GH6, 4Y87, and 6LZZ) were analyzed for physicochemical properties, structural validation, and binding site prediction. Pharmacophore-guided virtual screening of PubChem-derived compounds was followed by active–decoy validation, ADMET evaluation, molecular docking, redocking validation, protein–ligand interaction analysis, and 500 ns molecular dynamics simulations. Several compounds demonstrated favorable binding affinities and pharmacokinetic profiles. Among them, EVPMO-PurHD exhibited the strongest binding affinity (− 10.1 kcal/mol) and suggested stable interaction behavior during the equilibrated phase of the simulation, following an initial conformational adjustment period, as indicated by RMSD stabilization and sustained intermolecular interaction. The findings indicate that the identified compounds represent promising computationally predicted candidates for PDE9A inhibition, supported by favorable binding affinity, stability, and pharmacokinetic profiles. However, further experimental validation through biochemical and in vitro/in vivo studies is required to confirm their therapeutic potential.