4D09

PDE2a catalytic domain in complex with a brain penetrant inhibitor

4D09 の概要

• エントリーDOI: 10.2210/pdb4d09/pdb
• 関連するPDBエントリー: 4D08
• 分子名称: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE, N-benzyl-4-methyl-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, cyclic nucleotide phosphodiesterases, type 2, type 4, disease models, animal, drug evaluation, preclinical, phosphodiesterase 2 inhibitors, phosphodiesterase inhibitors, protein binding, structure-activity relationship
• 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: 4
• 化学式量合計: 167662.12

構造登録者

Buijnsters, P.,Andres, J.I.,DeAngelis, M.,Langlois, X.,Rombouts, F.,Sanderson, W.,Tresadern, G.,Trabanco, A.,VanHoof, G.,VanRoosbroeck, Y. (登録日: 2014-04-24, 公開日: 2014-08-06, 最終更新日: 2024-05-01)

主引用文献

Buijnsters, P.,De Angelis, M.,Langlois, X.,Rombouts, F.J.R.,Sanderson, W.,Tresadern, G.,Ritchie, A.,Trabanco, A.A.,Vanhoof, G.,Roosbroeck, Y.V.,Andres, J.
Structure-Based Design of a Potent, Selective, and Brain Penetrating Pde2 Inhibitor with Demonstrated Target Engagement.
Acs Med.Chem.Lett., 5:1049-, 2014

PubMed Abstract: Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.

PubMed: 25221665
DOI: 10.1021/ML500262U

実験手法

X-RAY DIFFRACTION (2.5 Å)