Selectivity Searching for Cathepsin K-Selective Inhibitors

For selectivity searching, three enzymes, cathepsins K, L, and S, were targeted and cathepsin K inhibitors selective for K over L and S were used as reference molecules in order to identify new cathepsin K-selective inhibitors [43]. 

The cathepsin enzymes are cysteine proteases belonging to the papain superfamily [59] and are closely related to each other with sequence identities of 56-60% (cathepsins K and L 60%, S and K 57%, and S and L 56% [60]). In addition to overall high sequence similarity, the active sites have a high degree of conservation. 

Cathepsin inhibitors are typically substrate analogues containing a strong electrophilic group (a hallmark of these inhibitors), which covalently modify the active site cysteine. Recently, reversible covalent inhibitors have also been introduced with a less-reactive functional group, typically a nitrile, which renders these inhibitors reversible. However, these compounds still form a covalent yet reversible bond with the catalytic cysteine residue. 

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