Pharmacoinformatics Study and High-Throughput Virtual Screening to Discover Effective Natural Compounds in Treatment of Erectile Dysfunction

Erectile dysfunction (ED) is the consistent or recurrent inability to achieve and/or maintain penile erectionsufficient for a satisfying sexual performance. It is expected that ≈۳۲۲ million men worldwide will sufferfrom ED by ۲۰۲۵. Phosphodiesterase ۵ (PDE۵) is a well-studied enzyme that specifically targets cGMPproduced by nitric oxide-mediated activation of the guanylyl cyclase. Considering the crucial function ofcGMP generated through the activation of this signaling pathway in several physiological processes,pharmacological inhibition of PDE۵ has been revealed to be beneficial in ED treatment. Sildenafil was thefirst PDE۵ inhibitor that showed a wonderful efficacy in ED, but it can still cause several side effects. Here,we used a library of ۱۲۲۸ purchasable natural products to investigate their inhibitory effect on PDE۵ throughbioinformatics tools and databases. Primarily, the three-dimensional structure of PDE۵ was downloaded fromthe "Protein Data Bank" database, containing the crystal structure of the enzyme together with its inhibitor,Sildenafil. Structure preparation for docking was performed using the UCSF Chimera program, and ADTsoftware. Water molecules and Sildenafil were removed, and hydrogens were added to the structure. Then,docking between Sildenafil and PDE۵ was performed using AutoDock Vina software, to validate the gridbox and determine the positive control binding energy. Docking between PDE۵ and the library of naturalcompounds was carried out by AutoDock Vina software on the MTiOpenScreen server. The top ۲۰compounds were later evaluated by the Lipinski rule, and five compounds that followed the rule wereassessed for toxicity. Finally, Alpha-Spinasterol glucoside (Affinity = -۱۱.۱ (kcal/mol)) and Yuccagenin(Affinity = -۱۱ (kcal/mol)) were chosen as the leading compounds, and the ADME properties of them wereevaluated through the pkCSM server. After pharmacokinetics studies, we concluded that Alpha-Spinasterolglucoside and Yuccagenin as PDE۵ inhibitors can be candidates for the treatment of ED.

کلیدواژه ها:

Alpha-Spinasterol glucoside ، Erectile dysfunction ، Phosphodiesterase ۵ ، Sildenafil ، Yuccagenin