6F7Q

Human Butyrylcholinesterase complexed with N-Propargyliperidines

6F7Q の概要

• エントリーDOI: 10.2210/pdb6f7q/pdb
• 分子名称: Cholinesterase, SULFATE ION, CHLORIDE ION, ... (12 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: 126208.40

構造登録者

Coquelle, N.,Knez, D.,Colletier, J.P.,Gobec, S. (登録日: 2017-12-11, 公開日: 2018-09-05, 最終更新日: 2025-10-01)

主引用文献

Knez, D.,Coquelle, N.,Pislar, A.,Zakelj, S.,Jukic, M.,Sova, M.,Mravljak, J.,Nachon, F.,Brazzolotto, X.,Kos, J.,Colletier, J.P.,Gobec, S.
Multi-target-directed ligands for treating Alzheimer's disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities.
Eur.J.Med.Chem., 156:598-617, 2018

PubMed Abstract: The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Aβ species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.

PubMed: 30031971
DOI: 10.1016/j.ejmech.2018.07.033

実験手法

X-RAY DIFFRACTION (2.6 Å)