6ZWI

Human butyrylcholinesterase in complex with ((6-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamido)hexyl)triphenylphosphonium bromide)

6ZWI の概要

• エントリーDOI: 10.2210/pdb6zwi/pdb
• 分子名称: Cholinesterase, CHLORIDE ION, SULFATE ION, ... (13 entities in total)
• 機能のキーワード: butyrylcholinesterase, inhibitor, mitochondria, 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: 64474.36

構造登録者

Da Silva, O.,Nachon, F.,Dias, J.,Brazzolotto, X. (登録日: 2020-07-28, 公開日: 2021-06-09, 最終更新日: 2024-11-06)

主引用文献

Chavarria, D.,Da Silva, O.,Benfeito, S.,Barreiro, S.,Garrido, J.,Cagide, F.,Soares, P.,Remiao, F.,Brazzolotto, X.,Nachon, F.,Oliveira, P.J.,Dias, J.,Borges, F.
Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases.
Antioxidants (Basel), 10:-, 2021

PubMed Abstract: Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP) conjugates (compounds -), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (BChE) and moderate electric eel acetylcholinesterase (AChE) inhibitors, with catechols 4 and 5 presenting lower IC values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds - towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds - in complex with human ChEs (ChEs) showed that these compounds exhibit different binging modes to AChE and BChE. Unlike AntiOXCINs, compounds - displayed moderate human monoamine oxidase (MAO) inhibitory activity. Moreover, compounds and presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.

PubMed: 33672269
DOI: 10.3390/antiox10020329

実験手法

X-RAY DIFFRACTION (1.85 Å)