4Y86

Crystal structure of PDE9 in complex with racemic inhibitor C33

Summary for 4Y86

• Entry DOI: 10.2210/pdb4y86/pdb
• Related: 4Y87
• Descriptor: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, 6-{[(1S)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, ZINC ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterase 9a, inhibitor selectivity pocket, pharmacokinetics, enantiomeric differentiation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 124473.26

Authors

Huang, M. (deposition date: 2015-02-16, release date: 2015-09-16, Last modification date: 2024-02-28)

Primary citation

Huang, M.,Shao, Y.,Hou, J.,Cui, W.,Liang, B.,Huang, Y.,Li, Z.,Wu, Y.,Zhu, X.,Liu, P.,Wan, Y.,Ke, H.,Luo, H.B.
Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.
Mol.Pharmacol., 88:836-845, 2015

PubMed Abstract: Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

PubMed: 26316540
DOI: 10.1124/mol.115.099747

Experimental method

X-RAY DIFFRACTION (2.01 Å)