5B4K

Crystal structure of the catalytic domain of human PDE10A complexed with N-(4-((5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy)phenyl)-1H-benzimidazol-2-amine

5B4K の概要

• エントリーDOI: 10.2210/pdb5b4k/pdb
• 関連するPDBエントリー: 5B4L
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, MAGNESIUM ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: 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: 78671.36

構造登録者

Oki, H.,Zama, Y. (登録日: 2016-04-05, 公開日: 2016-06-29, 最終更新日: 2023-11-08)

主引用文献

Yoshikawa, M.,Hitaka, T.,Hasui, T.,Fushimi, M.,Kunitomo, J.,Kokubo, H.,Oki, H.,Nakashima, K.,Taniguchi, T.
Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket
Bioorg.Med.Chem., 24:3447-3455, 2016

PubMed Abstract: Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs.

PubMed: 27301679
DOI: 10.1016/j.bmc.2016.05.049

実験手法

X-RAY DIFFRACTION (2.9 Å)