5LKR

Human Butyrylcholinesterase complexed with N-Propargyliperidines

5LKR の概要

• エントリーDOI: 10.2210/pdb5lkr/pdb
• 分子名称: Cholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: alzheimer disease ad butyrylcholinesterase n-propargyliperidines, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 136625.29

構造登録者

Coquelle, N.,Knez, D.,Colletier, J.P.,Gobec, S. (登録日: 2016-07-23, 公開日: 2016-12-14, 最終更新日: 2024-10-16)

主引用文献

Kosak, U.,Knez, D.,Coquelle, N.,Brus, B.,Pislar, A.,Nachon, F.,Brazzolotto, X.,Kos, J.,Colletier, J.P.,Gobec, S.
N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents.
Bioorg. Med. Chem., 25:633-645, 2017

PubMed Abstract: In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.

PubMed: 27908752
DOI: 10.1016/j.bmc.2016.11.032

実験手法

X-RAY DIFFRACTION (2.52 Å)