Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis.

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Wang H, Luo X, Ye M, Hou J, Robinson H, Ke H

Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis.

J Med Chem. 2010 Feb 25;53(4):1726-31. doi: 10.1021/jm901519f.

PubMed ID

20121115 [ View in PubMed

]

Abstract

PDE9 inhibitors have been studied as therapeutics for treatment of cardiovascular diseases, diabetes, and neurodegenerative disorders. To illustrate the inhibitor selectivity, the crystal structures of the PDE9A catalytic domain in complex with the enantiomers of PDE9 inhibitor 1-(2-chlorophenyl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidin e-4(5H)-one ((R)-BAY73-6691 or (S)-BAY73-6691, 1r or 1s) were determined and mutagenesis was performed. The structures showed that the fluoromethyl groups of 1r and 1s had different orientations while the other parts of the inhibitors commonly interacted with PDE9A. These differences may explain the slightly different affinity of 1r (IC(50) = 22 nM) and 1s (IC(50) = 88 nM). The mutagenesis experiments revealed that contribution of the binding residues to the inhibitor sensitivity varies dramatically, from few-fold to 3 orders of magnitude. On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A	O76083	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
3-isobutyl-1-methyl-7H-xanthine	High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A	IC 50 (nM)	>200000	N/A	N/A	Details