4OC6

Structure of Cathepsin D with inhibitor 2-bromo-N-[(2S,3S)-4-{[2-(2,4-dichlorophenyl)ethyl][3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]amino}-3-hydroxy-1-(3-phenoxyphenyl)butan-2-yl]-4,5-dimethoxybenzamide

Summary for 4OC6

• Entry DOI: 10.2210/pdb4oc6/pdb
• Related: 1LYA 4OBZ 4OD9
• Descriptor: Cathepsin D light chain, Cathepsin D heavy chain, alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: lysosomal aspartic protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 39765.72

Authors

Graedler, U.,Czodrowski, P.,Tsaklakidis, C.,Klein, M.,Maskos, K.,Leuthner, B. (deposition date: 2014-01-08, release date: 2014-08-13, Last modification date: 2024-11-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.64 Å)