4P6G: Crystal Structure Of Human Cathepsin S Bound To A Non-covalent Inhibitor

Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.
PDB ID: 4P6GDownload
MMDB ID: 124330
PDB Deposition Date: 2014/3/24
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 1.58  Å
Source Organism:
Similar Structures:
Biological Unit for 4P6G: monomeric; determined by author
Molecular Components in 4P6G
Label Count Molecule
Protein (1 molecule)
Cathepsin S(Gene symbol: CTSS)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB