4GH6

Crystal structure of the PDE9A catalytic domain in complex with inhibitor 28

Summary for 4GH6

• Entry DOI: 10.2210/pdb4gh6/pdb
• Descriptor: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A, N-(4-methoxyphenyl)-N~2~-[1-(2-methylphenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-L-alaninamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: pde9a, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform PDE9A1: Cell projection, ruffle membrane. Isoform PDE9A2: Cell projection, ruffle membrane. Isoform PDE9A3: Cytoplasm. Isoform PDE9A17: Cytoplasm: O76083
• Total number of polymer chains: 2
• Total formula weight: 78527.91

Authors

Hou, J.,Ke, H. (deposition date: 2012-08-07, release date: 2012-10-03, Last modification date: 2024-02-28)

Primary citation

Meng, F.,Hou, J.,Shao, Y.X.,Wu, P.Y.,Huang, M.,Zhu, X.,Cai, Y.,Li, Z.,Xu, J.,Liu, P.,Luo, H.B.,Wan, Y.,Ke, H.
Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design.
J.Med.Chem., 55:8549-8558, 2012

PubMed Abstract: A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC(50) of 21 nM and 3.3 μM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.

PubMed: 22985069
DOI: 10.1021/jm301189c

Experimental method

X-RAY DIFFRACTION (2.7 Å)