Deciphering phosphodiesterase-5 inhibitors from Aframemum melegueta: computational models against erectile dysfunction.

Insufficient and inability to maintain erection in male for satisfactory sexual performance remains global challenge among couples. The identification of phosphodiesterase-5 (PDE-5) antagonist in the pathogenesis of erectile dysfunction has improved the search for therapeutic agents for the management of this sexual dysfunction. Here in, bioactive compounds from Aframomum melegueta were virtually screened against PDE-5 using Schrodinger suite 2017-1 as computational tool. The lead compound was further validated in comparison with sildenafil by performing 100 ns molecular dynamics (MD) simulation using Desmond. Among 109 bioactive compounds screened, nine (9) molecules were predicted as potent inhibitors of PDE-5 with binding affinities comparable to the co-crystalized ligand (sildenafil). 1,7-bis(3,4-dihyroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate was observed to have the best docking score (-11.522 kcal/mol) among the hit compounds which is very close to the co-crystalized ligand (-11.872 kcal/mol). Validation using pharmacophore hypothesis and QSAR modeling further confirmed the prediction of the hit compounds with fitness score ranging from 0.754 to 2.605 and predicted pIC50 of 3.835 to 7.976 µM. All the hit compounds obeyed Lipinski's rule of five and within the reference range of the pharmacokinetics parameters. The MD simulation result predicted the stability of 1,7-bis(3,4-dihydroxy-5-methoxyphenyl)heptane-3,5-diyldiacetate-PDE-5 complex comparable to the sildenafil-PDE-5 complex. The outcome of this study predicted nine molecules from A. melegueta as potent PDE-5 antagonists which required isolation and experimental validation for the management of erectile dysfunction.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00284-3.