Inhibition of cathepsin B by Au(I) complexes

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Subtitle: a kinetic and computational study
Author list: Gunatilleke SS, de Oliveira CAF, McCammon JA, Barrios AM
Publisher: Springer Verlag (Germany)
Publication year: 2008
Volume number: 13
Issue number: 4
Start page: 555
End page: 561
Number of pages: 7
ISSN: 0949-8257
Languages: English-Great Britain (EN-GB)


Gold(I) compounds have been used in the treatment of rheumatoid arthritis for over 80 years, but the biological targets and the structure-activity relationships of these drugs are not well understood. Of particular interest is the molecular mechanism behind the antiarthritic activity of the orally available drug triethylphosphine(2,3,4,6-tetra-O-acetyl-beta-1-D-thiopyranosato-S) gold(I) (auranofin, Ridaura). The cathepsin family of lysosomal, cysteine-dependent enzymes is an attractive biological target of Au(I) and is inhibited by auranofin and auranofin analogs with reasonable potency. Here we employ a combination of experimental and computational investigations into the effect of changes in the phosphine ligand of auranofin on its in vitro inhibition of cathepsin B. Sequential replacement of the ethyl substituents of triethylphosphine by phenyl groups leads to increasing potency in the resultant Au(I) complexes, due in large part to favorable interactions of the more sterically bulky Au(I)-PR3 fragments with the enzyme active site.


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Last updated on 2019-23-08 at 11:15