Computational exploration of aphrodisiac potential: identifying inhibitors from Tribulus terrestris L., and Securidaca longepedunculata targeting human phosphodiesterase 5.

Impotence, also referred to as Erectile Dysfunction (ED), is a sexual health condition that affects a large number of men globally. The Food and Drug Administration (FDA) recommends Sildenafil citrate (Viagra®, Pfizer, New York, NY, USA) as a treatment for erectile dysfunction. Regretfully, heart failure, headaches, dizziness, blurred vision, irregular heartbeat, dyspepsia, and priapism have been reported as the main adverse effects of using Sildenafil citrate. Additionally, the cost is also exorbitant. Recent records suggest that certain compounds derived from phytochemical sources possess aphrodisiac qualities and can successfully treat erectile dysfunction without causing significant side effects. Thus, the focus of this work is to computationally investigate drug-target binding affinities and interactions at atomic levels using in silico techniques such as molecular docking, ADMET analysis, and molecular dynamics simulation. A total of 12 reported compounds (including one registered drug, which was used as a standard) exhibiting aphrodisiac qualities were docked with the crystal structures of the Human Phosphodiesterase 5 enzyme (PDB IDs: 1UDT, 1UHO, and 2CHM). When compared to the standard, all 11 compounds demonstrated good binding geometry and binding affinity scores. Of the 11 compounds selected for the best possible posing with the receptor, 6 satisfied Lipinski's rule of five. Following the completion of the ADMET studies, it was found that TanF (5-p-coumaroylquinic), TanI (Harmane), and XanA (1,3,6-trihydroxy-2,5-dimethoxyxanthone) had better pharmacokinetic properties than the standard. Molecular dynamics simulations and free energy calculations were used to determine the relative stability of the selected three potential compounds. The comprehensive results confirm that TanF, TanI, and XanA are more suitable candidates for the treatment of erectile dysfunction than the current medication, Sildenafil citrate. These findings suggest that natural product-derived compounds may serve as safer and more effective alternatives for erectile dysfunction therapy.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00402-9.