Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study
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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-β-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.
KeywordsEnzyme inhibition Gold Chrysotherapy Cathepsins Molecular modeling
A.M.B. and S.S.G. acknowledge the College of Letters, Arts and Sciences and the WiSE program at the University of Southern California for generous support. The work done by C.A.F.O. and J.A.M. was supported in part by grants from NSF, NIH, the Center for Theoretical Biological Physics, the National Biomedical Computation Resource, San Diego Supercomputing Center and Accelrys Inc.
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