5U7D

PDE2 catalytic domain complexed with inhibitors

5U7D の概要

• エントリーDOI: 10.2210/pdb5u7d/pdb
• 関連するPDBエントリー: 5U7I 5U7J 5U7K 5U7L
• 分子名称: cGMP-dependent 3',5'-cyclic phosphodiesterase, 2-(3,4-dimethoxybenzyl)-7-[(2R,3R)-2-hydroxy-6-phenylhexan-3-yl]-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one, ZINC ION, ... (5 entities in total)
• 機能のキーワード: pde2, sbdd, inhibitor, phosphodiesterase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform PDE2A3: Cell membrane ; Lipid-anchor . Isoform PDE2A2: Mitochondrion matrix . Isoform PDE2A1: Cytoplasm . Isoform 5: Mitochondrion : O00408
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 122374.15

構造登録者

Pandit, J.,Parris, K. (登録日: 2016-12-12, 公開日: 2017-06-28, 最終更新日: 2023-10-04)

主引用文献

Helal, C.J.,Arnold, E.P.,Boyden, T.L.,Chang, C.,Chappie, T.A.,Fennell, K.F.,Forman, M.D.,Hajos, M.,Harms, J.F.,Hoffman, W.E.,Humphrey, J.M.,Kang, Z.,Kleiman, R.J.,Kormos, B.L.,Lee, C.W.,Lu, J.,Maklad, N.,McDowell, L.,Mente, S.,O'Connor, R.E.,Pandit, J.,Piotrowski, M.,Schmidt, A.W.,Schmidt, C.J.,Ueno, H.,Verhoest, P.R.,Yang, E.X.
Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.
J. Med. Chem., 60:5673-5698, 2017

PubMed Abstract: Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.

PubMed: 28574706
DOI: 10.1021/acs.jmedchem.7b00397

実験手法

X-RAY DIFFRACTION (1.75 Å)