Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.

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Sung BJ, Hwang KY, Jeon YH, Lee JI, Heo YS, Kim JH, Moon J, Yoon JM, Hyun YL, Kim E, Eum SJ, Park SY, Lee JO, Lee TG, Ro S, Cho JM

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.

Nature. 2003 Sep 4;425(6953):98-102.

PubMed ID

12955149 [ View in PubMed

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Abstract

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Vardenafil	cGMP-specific 3',5'-cyclic phosphodiesterase	Protein	Humans	Yes	Inhibitor	Details

Polypeptides

Name	UniProt ID
cGMP-specific 3',5'-cyclic phosphodiesterase	O76074	Details