Virtual Screening of Phytochemicals From Medicinal Plants as Promising PDE5 Inhibitors Against Erectile Dysfunction

ABSTRACT This study evaluates bioactive phytochemicals from Algerian medicinal plants as potential phosphodiesterase‐5 (PDE5) inhibitors for the treatment of erectile dysfunction (ED) using an integrated in silico approach. A total of 76 compounds from 48 plant species were screened for drug‐likeness using SwissADME. Overall, 72% of the compounds complied with Lipinski's Rule of Five, indicating favorable oral bioavailability, while toxicity prediction identified 29 non‐toxic candidates. Molecular docking was validated by redocking the co‐crystallized PDE5 ligand (RMSD = 0.264 Å). Ellagic acid (−9.4 kcal·mol −1 ), rosmarinic acid (−9.2 kcal·mol −1 ), salvinorin A (−9.2 kcal·mol −1 ), and catechin (−9.0 kcal·mol −1 ) exhibited the strongest binding affinities. Molecular dynamics simulations revealed stable hydrogen‐bond interactions for rosmarinic acid, while salvinorin A showed compact and low‐fluctuation behavior. MM‐GBSA analysis confirmed favorable binding free energies for salvinorin A (−26.7 kcal·mol −1 ) and rosmarinic acid (−23.6 kcal·mol −1 ). A QSAR model based on docking‐derived pKd values and molecular descriptors showed strong predictive performance using Random Forest regression ( R 2 train = 0.91; R 2 CV = 0.87), identifying LogP, molecular weight, and TPSA as key determinants of PDE5 inhibition. Overall, this study highlights catechin and related phytochemicals as promising natural PDE5 inhibitors, supporting their further preclinical evaluation as safer and affordable ED therapies.