7CM0

Crystal structure of a glutaminyl cyclase in complex with NHV-1009

7CM0 の概要

• エントリーDOI: 10.2210/pdb7cm0/pdb
• 分子名称: Glutaminyl-peptide cyclotransferase, 1-(cyclopentylmethyl)-1-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]-3-[3-(5-methylimidazol-1-yl)propyl]urea, ZINC ION, ... (4 entities in total)
• 機能のキーワード: glutaminyl cyclases (qcs), alzheimer disease, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 151857.19

構造登録者

Lee, J.W.,Song, J.Y.,Jang, T.H.,Ha, J.H. (登録日: 2020-07-23, 公開日: 2021-12-22, 最終更新日: 2024-10-23)

主引用文献

Van Manh, N.,Hoang, V.H.,Ngo, V.T.H.,Ann, J.,Jang, T.H.,Ha, J.H.,Song, J.Y.,Ha, H.J.,Kim, H.,Kim, Y.H.,Lee, J.,Lee, J.
Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design.
Eur.J.Med.Chem., 226:113819-113819, 2021

PubMed Abstract: The inhibition of glutaminyl cyclase (QC) may provide a promising strategy for the treatment of early Alzheimer's disease (AD) by reducing the amount of the toxic pyroform of β-amyloid (Aβ) in the brains of AD patients. In this work, we identified potent QC inhibitors with subnanomolar IC values that were up to 290-fold higher than that of PQ912, which is currently being tested in Phase II clinical trials. Among the tested compounds, the cyclopentylmethyl derivative (214) exhibited the most potent in vitro activity (IC = 0.1 nM), while benzimidazole (227) showed the most promising in vivo efficacy, selectivity and druggable profile. 227 significantly reduced the concentration of pyroform Aβ and total Aβ in the brain of an AD animal model and improved the alternation behavior of mice during Y-maze tests. The crystal structure of human QC (hQC) in complex with 214 indicated tight binding at the active site, supporting that the specific inhibition of QC results in potent in vitro and in vivo activity. Considering the recent clinical success of donanemab, which targets Aβ, small molecule-based QC inhibitors may also provide potential therapeutic options for early-stage AD treatment.

PubMed: 34536669
DOI: 10.1016/j.ejmech.2021.113819

実験手法

X-RAY DIFFRACTION (2.2 Å)