Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby regulating
the cyclic nucleotide signalling pathways and biological responses. PDEs inhibitors can be used clinically
for treatment of several diseases including central nervous system disorders, erectile dysfunction,
pulmonary hypertension, acute refractory cardiac failure, and inflammatory diseases such as chronic
obstructive pulmonary disease. However, the unfavourable risk-benefit ratio and side-effect profiles of
non-selective PDEs inhibitors have impeded their therapeutic success and therefore spurred the pharmaceutical
industry to develop family-selective PDE inhibitors. Given the recent remarkable advances
in structure-based drug design, this review will summarize developments and achievements in structure-based search, design
and optimization of PDEs inhibitors, and highlight the challenges that need to be addressed.
Keywords: Crystal structure, Cyclic nucleotide signalling pathway, Family-selective inhibitor, Medicinal chemistry, Phosphodiesterases,
Structure-based drug design.
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