7QHD

Human Butyrylcholinesterase in complex with (S)-1-(4-((2-(1H-indol-3-yl)ethyl)carbamoyl)benzyl)-N-(3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperidine-3-carboxamide

7QHD の概要

• エントリーDOI: 10.2210/pdb7qhd/pdb
• 分子名称: Cholinesterase, CHLORIDE ION, 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: 64125.80

構造登録者

Brazzolotto, X.,Jing, L.,Zhan, P.,Liu, X.,Nachon, F. (登録日: 2021-12-12, 公開日: 2022-12-21, 最終更新日: 2024-02-07)

主引用文献

Jing, L.,Wei, W.,Meng, B.,Chantegreil, F.,Nachon, F.,Martinez, A.,Wu, G.,Zhao, H.,Song, Y.,Kang, D.,Brazzolotto, X.,Zhan, P.,Liu, X.
Rapid discovery and crystallography study of highly potent and selective butylcholinesterase inhibitors based on oxime-containing libraries and conformational restriction strategies.
Bioorg.Chem., 134:106465-106465, 2023

PubMed Abstract: Butyrylcholinesterase is regarded as a promising drug target in advanced Alzheimer's disease. In order to identify highly selective and potent BuChE inhibitors, a 53-membered compound library was constructed via the oxime-based tethering approach based on microscale synthesis. Although A2Q17 and A3Q12 exhibited higher BuChE selectivity versus acetylcholinesterase, the inhibitory activities were unsatisfactory and A3Q12 did not inhibit Aβ peptide self-induced aggregation. With A2Q17 and A3Q12 as leads, a novel series of tacrine derivatives with nitrogen-containing heterocycles were designed based on conformation restriction strategy. The results demonstrated that 39 (IC = 3.49 nM) and 43 (IC = 7.44 nM) yielded much improved hBuChE inhibitory activity compared to the lead A3Q12 (IC = 63 nM). Besides, the selectivity indexes (SI = AChE IC / BChE IC) of 39 (SI = 33) and 43 (SI = 20) were also higher than A3Q12 (SI = 14). The results of the kinetic study showed that 39 and 43 exhibited a mixed-type inhibition against eqBuChE with respective K values of 1.715 nM and 0.781 nM. And 39 and 43 could inhibit Aβ peptide self-induced aggregation into fibril. X-ray crystallography structures of 39 or 43 complexes with BuChE revealed the molecular basis for their high potency. Thus, 39 and 43 are deserve for further study to develop potential drug candidates for the treatment of Alzheimer's disease.

PubMed: 36933339
DOI: 10.1016/j.bioorg.2023.106465

実験手法

X-RAY DIFFRACTION (2.04 Å)