ZINCPharmer-Based Identification of Multi-Target Inhibitors for Erectile Dysfunction: Pharmacophore Virtual Screening and Molecular Docking of Commercially Available Compounds

Erectile dysfunction (ED) affects approximately 300 million men globally, with current phosphodiesterase-5 (PDE-5) inhibitors associated with cardiovascular complications, headache, and addiction potential. This study employed ZINCPharmer pharmacophore-based virtual screening to identify novel multi-target inhibitors from commercially available compounds addressing multiple ED pathophysiological pathways. Using established PDE-5 inhibitors as query templates, four hit compounds were evaluated through molecular docking against PDE-5, arginase, protein kinase C (PKC), and O-GlcNAc transferase (OGT). Compound 4 demonstrated superior multi-target binding performance with strongest PDE-5 affinity (-9.11 kcal/mol versus − 8.96 kcal/mol for sildenafil), exceptional O-GlcNAc transferase binding energy (-45.41 kcal/mol, surpassing sildenafil at -31.00 kcal/mol), and favorable PKC binding (-52.13 kcal/mol), indicating robust polypharmacological potential. Notably, its higher LD ₅₀ value (1000 mg/kg) suggests wider therapeutic window compared to Compound 1 (380 mg/kg), despite two Lipinski violations and low gastrointestinal absorption requiring optimization. Compound 1 exhibited remarkably favorable arginase binding energy (-3.63 kcal/mol), zero Lipinski violations, high gastrointestinal absorption, non-blood-brain barrier permeability, and minimal CYP ₄₅₀ inhibition. Toxicological predictions indicated hepatotoxicity for Compound 4 and nephrotoxicity for Compound 1, though both maintained favorable carcinogenicity, mutagenicity, and cytotoxicity profiles. These findings establish Compound 4 as a particularly promising multi-target candidate warranting optimization, while Compound 1 offers complementary drug-like advantages. Both compounds address multifactorial ED pathophysiology more comprehensively than current single-mechanism therapies, establishing foundation for experimental validation and medicinal chemistry optimization.