Phosphodiesterase- 5 (PDE5) Inhibitory Potential of Major Phytochemicals of Withania somnifera and Cardiospermum halicacabum: an in silico comparison with approved PDE5 inhibitors
Abstract
The second messenger cyclic guanosine monophosphate (cGMP) produced in penile smooth muscle cells is responsible for triggering and maintain erection of penis.Phosphodiesterase type 5 (PDE5) is an enzyme that hydrolyses cGMP leading to penile flaccidity.Oral phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, tadalafil and avanafil remain the current standard for first-line treatment for erectile dysfunction (ED).Withania somnifera and Cardiospermum halicacabum are medicinal plants that are traditionally being used orally for the treatment of erectile dysfunction without any scientific evidence for their bioactivity.To validate these claims and to identify potential active ingredients, 53 major phytochemicals of W. somnifera and C. halicacabum were docked against the active site of the crystal structure of PDE5.Standard drugs sildenafil, tadalafil and avanafil were served as positive controls for molecular docking.Docked complexes with binding energies similar or greater than standard drugs were further studied by carrying out 100 ns molecular dynamics simulations and in silico adsorption, distribution, metabolism, excretion and toxicity (ADMET) predictions.Steroidal lactone withaferin A of W. somnifera was identified as potent inhibitor of PDE5 with predicted binding energy greater than that of sildenafil and avanafil while having very high oral bioavailability and less toxicity.Several other withaferin derivatives of W. somnifera , apigenin and rutine of C.…
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