6qbs

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

spinqualitylabelsall models 6qbs, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6qbs is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: CA, CL, HVW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CATK_HUMAN Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:265800. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature. Function CATK_HUMAN Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Publication Abstract from PubMed Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation ( kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile. The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K.,Mons E, Jansen IDC, Loboda J, van Doodewaerd BR, Hermans J, Verdoes M, van Boeckel CAA, van Veelen PA, Turk B, Turk D, Ovaa H J Am Chem Soc. 2019 Feb 27;141(8):3507-3514. doi: 10.1021/jacs.8b11027. Epub 2019, Feb 14. PMID:30689386 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cathepsin 3D structures

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