Toward Natural Products-Based Drug Development for Erectile Dysfunction: A Molecular Candidate from Plant <i>Tribulus terrestris</i> Identified by an Integrated <i>In Silico</i> Study

Conventional pharmacological interventions for erectile dysfunction (ED) primarily rely on the phosphodiesterase-5 (PDE5) inhibitors such as sildenafil, tadalafil, vardenafil, and avanafil that have side effects despite their therapeutic effects. PDE5 is the primary cyclic guanosine monophosphate-degrading enzyme located in the smooth muscles of the corpus cavernosum in the penile tissue that helps in relieving erection. Natural products and phytochemicals are viable sources of molecular leads for drug discovery and development and, thus, offer prospects for innovation in ED treatment. This <i>in silico</i> study reports the screening of phytochemicals from the plant <i>Tribulus terrestris</i> with an eye to identify molecular candidates that inhibit PDE5. Natural products-based compounds that selectively target PDE5 are poised to be useful in clinical management of ED, and potentially with lesser side effects. The following top three phytochemicals identified from <i>T. terrestris</i> showed higher negative binding affinities for the PDE5 enzyme: diosgenin,dehydro (-11.1 kcal/mol), ruscogenin (-11.1 kcal/mol), and hecogenin (-10.3 kcal/mol) compared with the control drug sildenafil (-8.8 kcal/mol). Hydrogen bonds and Van der Waals interactions were the predominant forces influencing the interactions formed in the protein-ligand complexes. The ΔG_bind binding free energies for these top three phytochemicals, diosgenin,dehydro, ruscogenin, and hecogenin, were -19.99 ± 5.99 kcal/mol, -9.05 ± 5.16 kcal/mol, and -14.11 ± 5.33 kcal/mol, respectively. Importantly, diosgenin,dehydro, a saponin obtained from <i>T. terrestris</i>, was identified as a particularly promising candidate for PDE5 inhibition by virtue of its higher negative binding affinity and, therefore, displaying a potential in drug discovery and development for ED. In addition, <i>in silico</i> pharmacokinetic analysis and toxicity assessments support the prospects of these <i>T. terrestris</i>-derived phytochemicals for future <i>in vitro</i> and <i>in vivo</i> research for innovation in ED therapeutics.