PDBsum entry 4x6h

Hydrolase

PDB id: 4x6h

Contents

Protein chain

215 a.a.

Ligands

3XT-I37

SO4 ×6

Waters ×290

PDB id:

4x6h

Name:

Hydrolase

Title:

Development of n-(functionalized benzoyl)-homocycloleucyl- glycinonitriles as potent cathepsin k inhibitors.

Structure:

Cathepsin k. Chain: a. Fragment: unp residues 115-329. Synonym: cathepsin o,cathepsin o2,cathepsin x. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ctsk, ctso, ctso2. Expressed in: komagataella pastoris gs115. Expression_system_taxid: 644223

Resolution:

1.00Å R-factor: 0.155 R-free: 0.166

Authors:

J.Borisek,B.Mohar,M.Vizovisek,P.Sosnowski,D.Turk,B.Turk,M.Novic

Key ref:

J.Borišek et al. (2015). Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors. J Med Chem, 58, 6928-6937. PubMed id: 26280490 DOI: 10.1021/acs.jmedchem.5b00746

Date:

08-Dec-14 Release date: 23-Sep-15

Protein chain

P43235  (CATK_HUMAN) -  Cathepsin K from Homo sapiens

Seq: 329 a.a.

Struc: 215 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.22.38 - cathepsin K.
• Reaction: Broad proteolytic activity. With small-molecule substrates and inhibitors, the major determinant of specificity is P2, which is preferably Leu, Met > Phe, and not Arg.

DOI no: 10.1021/acs.jmedchem.5b00746

J Med Chem 58:6928-6937 (2015)

PubMed id: 26280490

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

J.Borišek, M.Vizovišek, P.Sosnowski, B.Turk, D.Turk, B.Mohar, M.Novič.

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.