Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study.

@article{citeulike:2350512, abstract = {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)-PR(3) fragments with the enzyme active site.}, address = {Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA.}, author = {Gunatilleke, Shamila S. and de Oliveira, Cesar A. and McCammon, J A. and Barrios, Amy M. }, citeulike-article-id = {2350512}, doi = {http://dx.doi.org/10.1007/s00775-008-0344-0}, issn = {0949-8257}, journal = {J Biol Inorg Chem}, keywords = {gold}, month = {February}, posted-at = {2008-02-07 22:35:22}, priority = {2}, title = {Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study.}, url = {http://dx.doi.org/10.1007/s00775-008-0344-0}, year = {2008} }

TY - JOUR ID - citeulike:2350512 L3 - citeulike-article-id:2350512 TI - Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study. JF - J Biol Inorg Chem AD - Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA. SN - 0949-8257 N2 - 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)-PR(3) fragments with the enzyme active site. KW - gold AU - Gunatilleke, Shamila AU - de Oliveira, Cesar AU - McCammon, J AU - Barrios, Amy PY - 2008/02/06/ UR - http://dx.doi.org/10.1007/s00775-008-0344-0 ER -