Molecular insights and ADMET profiling of iridoids as candidate leads for erectile dysfunction therapy
Abstract
Context: Erectile dysfunction (ED) significantly affects male psychosocial health and has an increasing incidence. Although phosphodiesterase 5 (PDEi-5) inhibitors are the first-line therapy, the occurrence of visual side effects resulting from cross-inhibition of the PDE-6 isoform limits their adoption. In this context, the plant Veronica anagallis-aquatica L. emerges as a promising source of bioactive therapeutic compounds. This work investigated the inhibitory potential and selectivity of eight iridoid glycosides from this species against PDE-5 and PDE-6. The results identified catalposide as the most potent ligand, exhibiting an affinity energy of -8.6 kcal/mol against PDE-5, surpassing the reference drug Vardenafil (-8.3 kcal/mol) and showing high selectivity towards PDE-6. Trajectory analyses confirmed the robustness of the catalposide-PDE-5 complex, which exhibited smaller structural fluctuations than the commercial control. Despite initial predictions indicating low oral bioavailability, structural optimization through increased sp3 fraction proved to be a viable strategy for enhancing membrane permeability. In conclusion, the findings position catalposide as a promising prototype for the development of more selective and safe drugs for the treatment of ED.
Methods: The two-dimensional structures of the ligands were constructed in Marvin JS and subjected to energy minimization using the semi-empirical PM7 method in MOPAC software. The preparation of macromolecules…
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