5NAP

Torpedo californica acetylcholinesterase in complex with a non-chiral donepezil-like inhibitor 17

5NAP の概要

• エントリーDOI: 10.2210/pdb5nap/pdb
• 分子名称: Acetylcholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: acetylcholinesterase, inhibitors, alzheimer's disease, donepezil analogues, green chemistry, hydrolase
• 由来する生物種: Tetronarce californica (Pacific electric ray)
• 細胞内の位置: Isoform H: Cell membrane; Lipid-anchor, GPI- anchor. Isoform T: Cell membrane; Peripheral membrane protein: P04058
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 63567.28

構造登録者

Caliandro, R.,Pesaresi, A.,Lamba, D. (登録日: 2017-02-28, 公開日: 2018-05-02, 最終更新日: 2024-10-23)

主引用文献

Caliandro, R.,Pesaresi, A.,Cariati, L.,Procopio, A.,Oliverio, M.,Lamba, D.
Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues.
J Enzyme Inhib Med Chem, 33:794-803, 2018

PubMed Abstract: Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with K values of 11.12 ± 2.88 and 29.86 ± 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of β-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity.

PubMed: 29651884
DOI: 10.1080/14756366.2018.1458030

実験手法

X-RAY DIFFRACTION (2.17 Å)