Comparative analysis of phosphodiesterase type 5 inhibitors and usnic acid: exploring therapeutic potential in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by increased pressure in the pulmonary arteries, frequently resulting in right ventricular hypertrophy and heart failure. Phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil ( SIL ), tadalafil ( TAD ), and avanafil ( AVA ), have demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH). The growing interest in natural compounds, like usnic acid ( UA ), a dibenzofuran derived from lichens, stems from their promising potential as complementary therapies in various medical conditions. This study investigates the potential of UA as a PDE5 inhibitor compared to SIL , TAD , and AVA through ADMET analysis, molecular docking, and molecular dynamic simulations. The ADMET analysis suggests significant plasma protein binding and an extended half-life for UA , perhaps improving retention relative to synthetic inhibitors. Molecular docking analyses indicate that UA establishes stable interactions with PDE5, exhibiting binding energies similar to those of synthetic inhibitors. Molecular dynamic simulations validate the stability of these interactions and suggest that UA reduces the flexibility of PDE5, enhancing its inhibitory potential. The results demonstrate that UA may have a potential synergistic effect with PDE5 inhibitors in treating PAH, offering a favorable toxicity profile, particularly regarding cardiotoxicity and neurotoxicity.