5UWF

Crystal structure of human PDE10A in complex with inhibitor 16d

5UWF の概要

• エントリーDOI: 10.2210/pdb5uwf/pdb
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, 9-[(1S)-2,2-difluorocyclopropane-1-carbonyl]-6-[(4-methoxyphenyl)methyl]-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one, ZINC ION, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q9Y233
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80087.01

構造登録者

Xu, R.,Cedervall, E.P.,Sridhar, V.,Barker, R.,Aertgeerts, K. (登録日: 2017-02-21, 公開日: 2017-04-26, 最終更新日: 2023-10-04)

主引用文献

Dyck, B.,Branstetter, B.,Gharbaoui, T.,Hudson, A.R.,Breitenbucher, J.G.,Gomez, L.,Botrous, I.,Marrone, T.,Barido, R.,Allerston, C.K.,Cedervall, E.P.,Xu, R.,Sridhar, V.,Barker, R.,Aertgeerts, K.,Schmelzer, K.,Neul, D.,Lee, D.,Massari, M.E.,Andersen, C.B.,Sebring, K.,Zhou, X.,Petroski, R.,Limberis, J.,Augustin, M.,Chun, L.E.,Edwards, T.E.,Peters, M.,Tabatabaei, A.
Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.
J. Med. Chem., 60:3472-3483, 2017

PubMed Abstract: A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.

PubMed: 28406621
DOI: 10.1021/acs.jmedchem.7b00302

実験手法

X-RAY DIFFRACTION (1.87 Å)