4OBZ

Structure of Cathepsin D with inhibitor 2-(3,4-dimethoxyphenyl)-N-[N-(4-methylbenzyl)carbamimidoyl]acetamide

4OBZ の概要

• エントリーDOI: 10.2210/pdb4obz/pdb
• 関連するPDBエントリー: 1LYA 4OC6 4OD9
• 分子名称: Cathepsin D light chain, Cathepsin D heavy chain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: lysosomal aspartic protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 76615.25

構造登録者

Graedler, U.,Czodrowski, P.,Tsaklakidis, C.,Klein, M.,Maskos, K.,Leuthner, B. (登録日: 2014-01-08, 公開日: 2014-08-13, 最終更新日: 2024-11-06)

主引用文献

Gradler, U.,Czodrowski, P.,Tsaklakidis, C.,Klein, M.,Werkmann, D.,Lindemann, S.,Maskos, K.,Leuthner, B.
Structure-based optimization of non-peptidic Cathepsin D inhibitors.
Bioorg.Med.Chem.Lett., 24:4141-4150, 2014

PubMed Abstract: We discovered a novel series of non-peptidic acylguanidine inhibitors of Cathepsin D as target for osteoarthritis. The initial HTS-hits were optimized by structure-based design using CatD X-ray structures resulting in single digit nanomolar potency in the biochemical CatD assay. However, the most potent analogues showed only micromolar activities in an ex vivo glycosaminoglycan (GAG) release assay in bovine cartilage together with low cellular permeability and suboptimal microsomal stability. This new scaffold can serve as a starting point for further optimization towards in vivo efficacy.

PubMed: 25086681
DOI: 10.1016/j.bmcl.2014.07.054

実験手法

X-RAY DIFFRACTION (2.9 Å)