7QBR

Human butyrylcholinesterase in complex with (Z)-N-tert-butyl-1-(8-(3-(4-(prop-2-yn-1-yl)piperazin-1-yl)propoxy)quinolin-2-yl)methanimine oxide

7QBR の概要

• エントリーDOI: 10.2210/pdb7qbr/pdb
• 分子名称: Cholinesterase, SULFATE ION, 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: butyrylcholinesterase, inhibitor, complex, 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: 63950.29

構造登録者

Denic, M.,Chioua, M.,Knez, D.,Gobec, S.,Nachon, F.,Marco-Contelles, J.L.,Brazzolotto, X. (登録日: 2021-11-19, 公開日: 2022-11-30, 最終更新日: 2024-10-16)

主引用文献

Knez, D.,Diez-Iriepa, D.,Chioua, M.,Gottinger, A.,Denic, M.,Chantegreil, F.,Nachon, F.,Brazzolotto, X.,Skrzypczak-Wiercioch, A.,Meden, A.,Pislar, A.,Kos, J.,Zakelj, S.,Stojan, J.,Salat, K.,Serrano, J.,Fernandez, A.P.,Sanchez-Garcia, A.,Martinez-Murillo, R.,Binda, C.,Lopez-Munoz, F.,Gobec, S.,Marco-Contelles, J.
8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.
Acta Pharm Sin B, 13:2152-2175, 2023

PubMed Abstract: We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN , a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC = 1.06 ± 0.31 nmol/L) and hMAO-B (IC = 4.46 ± 0.18 μmol/L). The crystal structures of with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, studies showed the anti-amnesic effect of in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1E9 mice with reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN .

PubMed: 37250172
DOI: 10.1016/j.apsb.2023.01.013

実験手法

X-RAY DIFFRACTION (2.13 Å)