Discovery of natural PDE-5 inhibitors in NO signalling pathways for the human erectile dysfunction management: a multi-layered in silico assessment.

PDE-5 enzyme plays a role in penile erection through cGMP hydrolysis in erectile dysfunction (ED), a prevalent urological illness with a complex pathogenesis. To identify potential phytochemical inhibitors targeting the PDE-5 enzyme, along with comparison of final hit with synthetic drug Sildenafil. Lipinski's drug-likeness filter was applied to phytochemicals retrieved from PubChem. These compounds were docked against the PDE-5 using AutoDock Vina and then redocking, followed by ADME/T and toxicity evaluation. A 100 ns MD simulations, and trajectory analyses was done. The electronic properties were assessed using DFT, and the binding free energies were calculated using MM/PBSA. Finally, the results were compared with Sildenafil, a reference drug. A total of 1152 phytochemicals were screened, out of which 515 passed drug-likeness filters. The top 100 compounds based on docking scores (upto - 9.8 kcal/mol) were shortlisted, redocking study suggested RMSD between 1.046 Å. A total 12 compounds showing favourable ADMET profiles, among them, four compounds were chosen for MD simulations. A stable engagement is indicated by RMSD values in the 0.16-0.79 nm range. MM/PBSA analysis revealed strong binding energies (- 17.01 to - 21.42 kcal/mol). Additionally, DFT studies showed HOMO-LUMO gaps between 3.93 and 6.39 eV, supporting electronic stability and potential bioactivity. The phytochemicals Daidzin, Maackiain, Rutecarpin, and Cyclopamine exhibited strong binding affinity with PDE-5, supported by stable MD simulations and favourable MM/PBSA energies. Their electronic stability and drug-like properties highlight their potential as natural PDE-5 enzyme inhibitors for ED management. All compounds have shown comparably equal results with Sildenafil. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00491-6.