6I0C

Human butyrylcholinesterase in complex with the R enantiomer of a chlorotacrine-tryptophan multi-target inhibitor.

6I0C の概要

• エントリーDOI: 10.2210/pdb6i0c/pdb
• 分子名称: Cholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: butyrylcholinesterase, hydrolase, multi-target inhibitor
• 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: 63006.14

構造登録者

Brazzolotto, X.,Nachon, F. (登録日: 2018-10-25, 公開日: 2019-03-27, 最終更新日: 2024-10-09)

主引用文献

Chalupova, K.,Korabecny, J.,Bartolini, M.,Monti, B.,Lamba, D.,Caliandro, R.,Pesaresi, A.,Brazzolotto, X.,Gastellier, A.J.,Nachon, F.,Pejchal, J.,Jarosova, M.,Hepnarova, V.,Jun, D.,Hrabinova, M.,Dolezal, R.,Zdarova Karasova, J.,Mzik, M.,Kristofikova, Z.,Misik, J.,Muckova, L.,Jost, P.,Soukup, O.,Benkova, M.,Setnicka, V.,Habartova, L.,Chvojkova, M.,Kleteckova, L.,Vales, K.,Mezeiova, E.,Uliassi, E.,Valis, M.,Nepovimova, E.,Bolognesi, M.L.,Kuca, K.
Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease.
Eur.J.Med.Chem., 168:491-514, 2019

PubMed Abstract: A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.

PubMed: 30851693
DOI: 10.1016/j.ejmech.2019.02.021

実験手法

X-RAY DIFFRACTION (2.675 Å)