4X6H: Development Of N-(functionalized Benzoyl)-homocycloleucyl- Glycinonitriles As Potent Cathepsin K Inhibitors

Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.
PDB ID: 4X6HDownload
MMDB ID: 132812
PDB Deposition Date: 2014/12/8
Updated in MMDB: 2015/09
Experimental Method:
x-ray diffraction
Resolution: 1  Å
Source Organism:
Similar Structures:
Biological Unit for 4X6H: monomeric; determined by author and by software (PISA)
Molecular Components in 4X6H
Label Count Molecule
Protein (1 molecule)
Cathepsin K(Gene symbol: CTSK)
Molecule annotation
Chemicals (8 molecules)
* Click molecule labels to explore molecular sequence information.

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