Supplementary file 1_Aildenafil citrate with superior PDE5 selectivity ameliorates cognitive and behavioral impairments in APP/PS1 Alzheimer’s disease mice: a preclinical phenotypic study.docx

Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment.</p>Methods<p>Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil.

The APP/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments.</p>Results<p>In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced π‐π stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments.