In silico ADMET Profiling of Flavonoids as Potential Phosphodiesterase-5 Inhibitors in the Management of Erectile Dysfunction

Abstract

Purpose: Erectile dysfunction (ED) affects millions of men globally, and its pharmacological management relies mainly on agents such as sildenafil, tadalafil, avanafil, and vardenafil. Although effective, these drugs are associated with adverse effects, creating a need for therapeutic alternatives with improved safety, efficacy, and bioavailability profiles. This study evaluated the preclinical absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of the flavonoids apigenin, kaempferol, and naringin as potential oral therapeutic candidates for ED. Methods: In silico ADMET profiling was conducted using SwissADME and ProTox-II to predict key pharmacokinetic and safety parameters, including solubility, gastrointestinal absorption, blood–brain barrier permeability, cytochrome P450 interactions, drug-likeness, and toxicity risks. Sildenafil served as the reference standard. Results: Apigenin and kaempferol exhibited favorable oral bioavailability and drug-likeness, consistent with Lipinski’s, Veber’s, Egan’s, and Muegge’s rules. These properties were supported by their optimal molecular weights, moderate topological polar surface areas, and minimal molecular flexibility (apigenin: 270.24 g/mol, TPSA 90.90 Å2; kaempferol: 286.24 g/mol, TPSA 111.13 Å2). Naringin, however, displayed limited absorption potential due to its higher molecular weight (580.53 g/mol) and large polar surface area (225.06 Å2). All compounds demonstrated acceptable predicted safety profiles, with no signals for mutagenicity or hepatotoxicity. Conclusion: The findings indicate that apigenin, kaempferol, and naringin may offer safer, more accessible alternatives or adjuncts to conventional ED medications such as sildenafil. Their favorable predicted pharmacokinetic and toxicity profiles support further exploration, and experimental validation in in vitro and in vivo models is recommended to confirm therapeutic potential.