4X6H

Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.

Summary for 4X6H

• Entry DOI: 10.2210/pdb4x6h/pdb
• Descriptor: Cathepsin K, 4-amino-3-fluoro-N-(1-{[(2Z)-2-iminoethyl]carbamoyl}cyclohexyl)benzamide, 4-amino-N-{1-[(cyanomethyl)carbamoyl]cyclohexyl}-3-fluorobenzamide, ... (5 entities in total)
• Functional Keywords: cathepsin k, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Lysosome: P43235
• Total number of polymer chains: 1
• Total formula weight: 24738.57

Authors

Borisek, J.,Mohar, B.,Vizovisek, M.,Sosnowski, P.,Turk, D.,Turk, B.,Novic, M. (deposition date: 2014-12-08, release date: 2015-09-23, Last modification date: 2024-01-10)

Primary citation

Borisek, J.,Vizovisek, M.,Sosnowski, P.,Turk, B.,Turk, D.,Mohar, B.,Novic, M.
Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.
J.Med.Chem., 58:6928-6937, 2015

PubMed Abstract: 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.

PubMed: 26280490
DOI: 10.1021/acs.jmedchem.5b00746

Experimental method

X-RAY DIFFRACTION (1 Å)