Identification of potential inhibitors of PDE5 based on structure-based virtual screening approaches

Abstract Cyclic adenosine monophosphate (cAMP) and cyclic guanidine monophosphate (cGMP) are the basis for understanding a large variety of physiological functions. Phosphodiesterase type 5 (PDE5), exclusively specific for cGMP, is mainly located in heart, lungs, smooth muscle cells and central nervous system, which can regulate intracellular levels of cGMP. Therefore, PDE5 is a potential target for the therapy of various diseases, and PDE5 inhibitors could be used as treatment for erectile dysfunction (ED) or chronic pulmonary hypertension. Herein, an integrated computer-aided virtual screening technique against the natural products in the ZINC database was used to discover PDE5 inhibitors. Pharmacophore, molecular docking and ADMET (Absorption, distribution, metabolism, excretion and toxicity) properties filtration were carried out to select the PDE5 inhibitors with best binding affinities and drug-like properties. The binding modes of PDE5-inhibitors were investigated and the stabilities of these complexes were explored by molecular dynamic simulations and MM/GBSA free energy calculations. The MM/GBSA free energy decomposition analysis quantitatively analyzed the importance of hydrophobic interaction in PDE5-ligands binding. As a result, two natural compounds were identified and may be used as critical starting point for development of novel PDE5 inhibitors. These results may promote the de novo design of new compounds against PDE5.