PDE5
July 2021
The phosphodiesterase enzyme type 5 (PDE5) is a member of a phosphodiesterase superfamily. It is responsible for the regulation of cyclic guanosine monophosphate (cGMP) specific signaling processes, including cellular growth, contractility, cardiovascular homeostasis, inflammation, and more. The PDE5’s function is to catalyze the hydrolysis of the phosphodiester bond in cGMP to the inactive N’-GMP. Being involved in critical cGMP signaling, PDE5 has been a promising drug target for many pathological processes. Nevertheless, only erectile dysfunction, lower urinary tract symptoms and pulmonary arterial hypertension are currently treated with the FDA- approved PDE5 inhibitors (sildenafil, vardenafil, tadalafil and avanafil).
PDE5 consists of a regulatory N-terminal and a catalytic C-terminal domain. The latter can be further divided into 3 helical subdomains. The active site is located in one of them – the C-terminal helical bundle - and is composed of 4 subpockets. The core pocket, called Q-pocket, is an interesting one because it accommodates the moiety of PDE5 inhibitors that mimics the guanidine group of the natural substrate cGMP. Moreover, the same core pocket bears 2 conserved residues - Gln817 and Phe820 – which form key interactions with the majority of PDE5 inhibitors. Gln817 often forms a bidentate hydrogen-bond while Phe820 forms an aromatic π-stack with the inhibitors’ scaffolds.
Interaction based search: on the left the interactions used as query and the parameters for the search are displayed, while on the right the reference structure (PDB ID: 4h24) and one of hit structures obtained from the search are superimposed in the 3D viewer. Sildenafil (showed in violet sticks) and RBN-2397 (showed in blue sticks) form the same interaction pattern (showed as dotted lines) respectively in PDE5 and in Protein mono-ADP-ribosyl transferase PARP12.
Recent studies showed that PDE5 inhibitors have high potential to treat more diseases than the current ones mentioned above. Their drug repurposing could be applied for the treatment of prostate enlargement, heart failure, neurodegenerative diseases, novel coronavirus disease (COVID19) and more. With the new 3decision protein-ligand interaction search feature, one can select the common interactions in the core pocket (for example the key interactions with Gln817 and Phe820) and search for a similar interaction pattern in other targets with available structural data. That way one can identify the complexes where PDE5 inhibitors might bind to. This could serve as a starting point for ligand design in drug re-purposing projects.
Reference: Ahmed WS, Geethakumari AM, Biswas KH. Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors. Biomed Pharmacother. 2021 Feb;134:111128. doi: 10.1016/j.biopha.2020.111128. Epub 2020 Dec 18. PMID: 33348311. https://doi.org/10.1016/j.biopha.2020.111128