7B8N

Notum-Fragment 197

7B8N の概要

• エントリーDOI: 10.2210/pdb7b8n/pdb
• 関連するPDBエントリー: 7B84
• 分子名称: Palmitoleoyl-protein carboxylesterase NOTUM, SULFATE ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: notum fragment, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44948.36

構造登録者

Zhao, Y.,Jonees, E.Y. (登録日: 2020-12-13, 公開日: 2022-01-12, 最終更新日: 2024-10-16)

主引用文献

Zhao, Y.,Mahy, W.,Willis, N.J.,Woodward, H.L.,Steadman, D.,Bayle, E.D.,Atkinson, B.N.,Sipthorp, J.,Vecchia, L.,Ruza, R.R.,Harlos, K.,Jeganathan, F.,Constantinou, S.,Costa, A.,Kjaer, S.,Bictash, M.,Salinas, P.C.,Whiting, P.,Vincent, J.P.,Fish, P.V.,Jones, E.Y.
Structural Analysis and Development of Notum Fragment Screening Hits.
Acs Chem Neurosci, 13:2060-2077, 2022

PubMed Abstract: The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 μM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1phenyl-1,2,3-triazole , and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound with IC 0.0067 μM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.

PubMed: 35731924
DOI: 10.1021/acschemneuro.2c00325

実験手法

X-RAY DIFFRACTION (1.56 Å)