7AWI

Crystal structure of human butyrylcholinesterase in complex with tert-butyl 3-(((2-((1-benzyl-1H-indol-4-yl)oxy)ethyl)amino)methyl]piperidine-1-carboxylate

7AWI の概要

• エントリーDOI: 10.2210/pdb7awi/pdb
• 分子名称: Cholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: butyrylcholinesterase, inhibitor complex, 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: 63017.80

構造登録者

Brazzolotto, X.,Goral, I.,Wieckowska, A. (登録日: 2020-11-08, 公開日: 2021-09-29, 最終更新日: 2024-11-13)

主引用文献

Wichur, T.,Godyn, J.,Goral, I.,Latacz, G.,Bucki, A.,Siwek, A.,Gluch-Lutwin, M.,Mordyl, B.,Sniecikowska, J.,Walczak, M.,Knez, D.,Jukic, M.,Salat, K.,Gobec, S.,Kolaczkowski, M.,Malawska, B.,Brazzolotto, X.,Wieckowska, A.
Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT 6 R antagonists with beta-amyloid anti-aggregation properties.
Eur.J.Med.Chem., 225:113792-113792, 2021

PubMed Abstract: The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT receptors and β-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC = 90 nM) and 5-HTR (K = 4.8 nM), and inhibitory activity against Aβ aggregation (53% at 10 μM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.

PubMed: 34530376
DOI: 10.1016/j.ejmech.2021.113792

実験手法

X-RAY DIFFRACTION (2.3 Å)