7D9O

Crystal Structure of Recombinant Human Acetylcholinesterase in Complex with Compound 2

7D9O の概要

• エントリーDOI: 10.2210/pdb7d9o/pdb
• 分子名称: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, (2R)-2-[[4-fluoranyl-1-[(4-fluorophenyl)methyl]piperidin-4-yl]methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one, ... (4 entities in total)
• 機能のキーワード: ache inhibitor, complex structure, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 123623.05

構造登録者

Liu, Q.F.,Yin, W.C. (登録日: 2020-10-14, 公開日: 2021-08-25, 最終更新日: 2024-10-16)

主引用文献

Zhou, Y.,Fu, Y.,Yin, W.,Li, J.,Wang, W.,Bai, F.,Xu, S.,Gong, Q.,Peng, T.,Hong, Y.,Zhang, D.,Zhang, D.,Liu, Q.,Xu, Y.,Xu, H.E.,Zhang, H.,Jiang, H.,Liu, H.
Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate.
J.Med.Chem., 64:1844-1855, 2021

PubMed Abstract: The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between and AChE. Besides, the data from the phase I trials demonstrated that had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

PubMed: 33570950
DOI: 10.1021/acs.jmedchem.0c01863

実験手法

X-RAY DIFFRACTION (2.45 Å)