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.
National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Jure
J
Borišek
Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
Matej
M
Vizovišek
Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
Piotr
P
Sosnowski
Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia.|Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
Boris
B
Turk
Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia.|Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.|Faculty of Chemistry and Chemical Technology, University of Ljubljana , Večna pot 113, SI-1000 Ljubljana, Slovenia.
Dušan
D
Turk
National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Barbara
B
Mohar
National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Marjana
M
Novič
D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D003515:Cycloleucine / Q000737:chemistry*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D001565:Benzoates; D004151:Dipeptides; D009570:Nitriles; D003515:Cycloleucine; D056657:Cathepsin K; D005998:Glycine