Phosphodiesterase 9: insights from protein structure and role in therapeutics

This review focuses on the development of drugs targeting phosphodiesterase 9A (PDE9A). PDE9A normally regulates cGMP (cyclic guanosine monophosphate) levels, which in turn regulate signal transduction. However, in pathological conditions, PDE9A inhibition is required to treat diseases that lower the level of cGMP. Hence, there is a need for specific PDE9A inhibitors. Aligning the 3D structure of PDE9A with other phosphodiesterases reveals residues crucial to inhibitor selectivity. GLU406 is unique to PDE9A and stabilizes the side chain of an invariant glutamine (GLN453). TYR424 is another relevant residue, unique only to PDE9A and PDE8A. Therefore, TYR424 could discriminate between PDE9A and all other PDEs except PDE8A. TYR424 should also be considered in the design of selective inhibitors because PDE8A has low expression levels in the brain. Hence, GLU406 and TYR424 are important target residues in the design of PDE9A-selective inhibitors.