4QGE

phosphodiesterase-9A in complex with inhibitor WYQ-C36D

4QGE の概要

• エントリーDOI: 10.2210/pdb4qge/pdb
• 分子名称: Phosphodiesterase 9A, N~2~-(1-cyclopentyl-4-oxo-4,7-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-(4-methoxyphenyl)-D-alaninamide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: pde9 catalytic domain, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Pan troglodytes (Chimpanzee)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 124550.47

構造登録者

Shao, Y.-X.,Huang, M.,Cui, W.,Ke, H. (登録日: 2014-05-22, 公開日: 2014-12-10, 最終更新日: 2024-11-20)

主引用文献

Shao, Y.X.,Huang, M.,Cui, W.,Feng, L.J.,Wu, Y.,Cai, Y.,Li, Z.,Zhu, X.,Liu, P.,Wan, Y.,Ke, H.,Luo, H.B.
Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent.
J.Med.Chem., 57:10304-10313, 2014

PubMed Abstract: Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer's disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.

PubMed: 25432025
DOI: 10.1021/jm500836h

実験手法

X-RAY DIFFRACTION (2 Å)