Abstract
Phosphodiesterase type 5 (PDE5) is an important enzyme associated with the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). Due to the relevant role of second messenger cGMP as a mediator in many physiological processes, efforts have been converged to find a safe pharmacological approach, seeking a specific, selective and potent inhibitor of the PDE5 enzyme. There are five commercial drugs with potential for clinical use: tadalafil, sildenafil, avanafil, udenafil and vardenafil. Here, we applied molecular modeling to obtain different profiles of protein–ligand interactions by adopting distinct PDE5 structures, specifically PDBid:1XOZ and two extracted from molecular dynamics (MD) simulations. The results generated by molecular docking showed several possibilities for inhibitor interactions with the catalytic pocket. Tadalafil, sildenafil and vardenafil were clearly stabilized by Gln817 via a well-oriented hydrogen bond. Another set of different interactions, such as polar, hydrophobic, π-stacking, metal–ligand and electrostatic, were responsible for accommodating avanafil and udenafil. All of the ligands are discussed in detail with consideration of the distinct protein structures, and a profile of the probability of residue–ligand contact is suggested, with the most frequently observed being: Tyr612, His613, Ser661, Thr723, Asp724, Asp764, Leu765, Val782 and Phe786. The molecular interactions displayed herein confirm findings achieved by previous authors and also present new contacts. In addition, the discussion can help researchers obtain a molecular basis for planning new selective PDE5 inhibitors, as well as explain an inhibitor’s experimental assays by considering the specific interactions occurring at the catalytic site.
Highlights
Phosphodiesterases (PDEs) are functionally distinct and highly regulated enzymes that have been classified into 11 families based on different genes in mammals [1]
It is known that the compounds discussed have high ability to interact with a specific region of the protein, the catalytic site, and prevent the hydrolysis of cyclic guanosine monophosphate (cGMP) [20,21,22,36]
The Phosphodiesterase type 5 (PDE5) enzyme has a number of subdomains within the catalytic pocket: (i) the M site, a metal-binding site for ions and residues around Mg2+ and Zn2+ ; (ii) the Q pocket, a central region of the catalytic site; (iii) the H pocket, a hydrophobic pocket; and (iv) the L region, a subdomain associated with catalytic site opening, named the lid region
Summary
Phosphodiesterases (PDEs) are functionally distinct and highly regulated enzymes that have been classified into 11 families based on different genes in mammals [1]. The intracellular cGMP produced has its cellular functions exerted by its binding to specific molecular targets, such as kinase proteins, ion channels, and phosphodiesterases [12]. These enzymes, especially PDE5, modulate the level of this second messenger and they are present in many tissues, including the corpus cavernosum [13], platelets [14], and vascular smooth muscle cells [14,15]
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