4GSF

The structure analysis of cysteine free insulin degrading enzyme (ide) with (s)-2-{2-[carboxymethyl-(3-phenyl-propionyl)-amino]-acetylamino}-3-(3h-imidazol-4-yl)-propionic acid methyl ester

4GSF の概要

• エントリーDOI: 10.2210/pdb4gsf/pdb
• 関連するPDBエントリー: 4GS8 4GSC 4GSE
• 分子名称: Insulin-degrading enzyme, methyl N-(carboxymethyl)-N-(3-phenylpropanoyl)glycyl-D-histidinate, ZINC ION, ... (4 entities in total)
• 機能のキーワード: insulin degrading enzyme, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P14735
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 230084.83

構造登録者

Guo, Q.,Deprez-Poulain, R.,Deprez, B.,Tang, W.J. (登録日: 2012-08-27, 公開日: 2013-08-28, 最終更新日: 2023-09-13)

主引用文献

Charton, J.,Gauriot, M.,Totobenazara, J.,Hennuyer, N.,Dumont, J.,Bosc, D.,Marechal, X.,Elbakali, J.,Herledan, A.,Wen, X.,Ronco, C.,Gras-Masse, H.,Heninot, A.,Pottiez, V.,Landry, V.,Staels, B.,Liang, W.G.,Leroux, F.,Tang, W.J.,Deprez, B.,Deprez-Poulain, R.
Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme.
Eur.J.Med.Chem., 90:547-567, 2015

PubMed Abstract: Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.

PubMed: 25489670
DOI: 10.1016/j.ejmech.2014.12.005

実験手法

X-RAY DIFFRACTION (2.7 Å)