4W63

TORPEDO CALIFORNICA ACETYLCHOLINESTERASE IN COMPLEX WITH A TACRINE-BENZOFURAN HYBRID INHIBITOR

4W63 の概要

• エントリーDOI: 10.2210/pdb4w63/pdb
• 分子名称: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: multitarget drug, enzyme-inhibitor complex, tacrine, benzofuran, hydrolase
• 由来する生物種: Torpedo californica (Pacific electric ray)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 61755.64

構造登録者

Pesaresi, A.,Samez, S.,Lamba, D. (登録日: 2014-08-20, 公開日: 2015-09-09, 最終更新日: 2024-11-13)

主引用文献

Zha, X.,Lamba, D.,Zhang, L.,Lou, Y.,Xu, C.,Kang, D.,Chen, L.,Xu, Y.,Zhang, L.,De Simone, A.,Samez, S.,Pesaresi, A.,Stojan, J.,Lopez, M.G.,Egea, J.,Andrisano, V.,Bartolini, M.
Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography.
J.Med.Chem., 59:114-131, 2016

PubMed Abstract: Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 μM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.

PubMed: 26632651
DOI: 10.1021/acs.jmedchem.5b01119

実験手法

X-RAY DIFFRACTION (2.8 Å)