5C2H

PDE10 complexed with 6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-[3-(2-quinolyl)propoxy]pyrimidin-4-amine

5C2H の概要

• エントリーDOI: 10.2210/pdb5c2h/pdb
• 関連するPDBエントリー: 5C1W 5C28 5C29 5C2A 5C2E
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: phosphodiesterase, inhibitor, complex, 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: 83974.79

構造登録者

Yan, Y. (登録日: 2015-06-15, 公開日: 2015-10-07, 最終更新日: 2024-11-20)

主引用文献

Shipe, W.D.,Sharik, S.S.,Barrow, J.C.,McGaughey, G.B.,Theberge, C.R.,Uslaner, J.M.,Yan, Y.,Renger, J.J.,Smith, S.M.,Coleman, P.J.,Cox, C.D.
Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.
J.Med.Chem., 58:7888-7894, 2015

PubMed Abstract: Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.

PubMed: 26378882
DOI: 10.1021/acs.jmedchem.5b00983

実験手法

X-RAY DIFFRACTION (2.09 Å)