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Binding mode of cyanohydrazide inhibitors targeting cathepsin K

28 March 2022
Binding mode of cyanohydrazide inhibitors targeting cathepsin K

Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors, but their binding mechanism remains unknown. 

The scientists led by Michael Mareš from IOCB Prague together with colleagues from the University of Bonn and Bonn Rhein-Sieg University of Applied Sciences investigated cyanohydrazide inhibitors with differently positioned warheads. They determined the crystal structures of covalent complexes of these inhibitors with CatK in the form of mature enzyme or its zymogen precursor. Binding mode analysis and quantum chemical calculations explained the extraordinary picomolar potency of cyanohydrazides.

The results provide structural insights for the rational design of potential drugs against pathologies associated with CatK.

Read the paper:

  • Benýšek, J.; Buša, M.; Rubešová, P.; Fanfrlík, J.; Lepšík, M.; Brynda, J.; Matoušková, Z.; Bartz, U.; Horn, M.; Gütschow, M.; Mareš, M. Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes. J. Enzyme Inhib. Med. Chem. 2022, 37, 515-526. 

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