7BGC

human butyrylcholinesterase in complex with a tacrine-methylanacardate hybrid inhibitor

7BGC の概要

• エントリーDOI: 10.2210/pdb7bgc/pdb
• 関連するPDBエントリー: 1p0i
• 分子名称: Cholinesterase, SULFATE ION, alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: inhibitor, alzheimer, butyrylcholinesterase, tacrine, anacardic acid, 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: 64038.95

構造登録者

Nachon, F.,Salerno, A.,Bolognesi, M.L. (登録日: 2021-01-06, 公開日: 2021-04-28, 最終更新日: 2024-11-13)

主引用文献

Rossi, M.,Freschi, M.,de Camargo Nascente, L.,Salerno, A.,de Melo Viana Teixeira, S.,Nachon, F.,Chantegreil, F.,Soukup, O.,Prchal, L.,Malaguti, M.,Bergamini, C.,Bartolini, M.,Angeloni, C.,Hrelia, S.,Soares Romeiro, L.A.,Bolognesi, M.L.
Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease.
J.Med.Chem., 64:4972-4990, 2021

PubMed Abstract: The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (, , and ), with subnanomolar activities. The X-ray crystal structure of complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for and (already at 0.01 μM), confirming the design rationale.

PubMed: 33829779
DOI: 10.1021/acs.jmedchem.1c00048

実験手法

X-RAY DIFFRACTION (2.4 Å)