5NR8

Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7a

5NR8 の概要

• エントリーDOI: 10.2210/pdb5nr8/pdb
• 分子名称: Chitotriosidase-1, 1-(3-azanyl-1~{H}-1,2,4-triazol-5-yl)-~{N}-[2-(4-bromophenyl)ethyl]-~{N}-methyl-piperidin-4-amine, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: chitotriosidase-1 (hchit) catalytic domain in complex with compound 7a, 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: 43156.15

構造登録者

Podjarny, A.,Fadel, F.,Golebiowski, A. (登録日: 2017-04-22, 公開日: 2018-02-21, 最終更新日: 2024-10-23)

主引用文献

Mazur, M.,Olczak, J.,Olejniczak, S.,Koralewski, R.,Czestkowski, W.,Jedrzejczak, A.,Golab, J.,Dzwonek, K.,Dymek, B.,Sklepkiewicz, P.L.,Zagozdzon, A.,Noonan, T.,Mahboubi, K.,Conway, B.,Sheeler, R.,Beckett, P.,Hungerford, W.M.,Podjarny, A.,Mitschler, A.,Cousido-Siah, A.,Fadel, F.,Golebiowski, A.
Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.
J. Med. Chem., 61:695-710, 2018

PubMed Abstract: This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.

PubMed: 29283260
DOI: 10.1021/acs.jmedchem.7b01051

実験手法

X-RAY DIFFRACTION (1.349 Å)