Novel Class of Bivalent Glutathione S-Transferase Inhibitors
- 15 August 2003
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 42 (35), 10418-10428
- https://doi.org/10.1021/bi0346188
Abstract
Exploiting the principle of bivalent binding, we have designed symmetrical, bifunctional inhibitors to simultaneously occupy both active sites of cytosolic glutathione S-transferase, with enhanced specificity for the P1-1 isoform. We have prepared two series of compounds that differ in their binding domainsthe first is a series of bis-glutathione conjugates, and the second is a series of compounds each possessing two equivalents of Uniblue A, an analogue of Cibacron Blue. For each series, a monofunctional reference compound was also prepared to determine the relative advantage of the bivalent inhibitors. Within each series, the most potent inhibitors exhibited IC50 values 2 orders of magnitude lower than the relevant reference compounds. Moreover, within the bis-glutathionyl series, a 10-fold increase in selectivity was achieved for GST P1-1 over the A1-1 isoform. Isothermal titration calorimetry with a representative bis-glutathione conjugate and a monofunctional reference compound indicates that the bivalent inhibitor exhibits the expected increase in intrinsic affinity and decrease in stoichiometry relative to the monofunctional compound, supporting the overall design strategy.Keywords
This publication has 3 references indexed in Scilit:
- The ligandin (non-substrate) binding site of human pi class glutathione transferase is located in the electrophile binding site (H-site)Journal of Molecular Biology, 1999
- Evaluation of methods for estimating the dissociation constant of tight binding enzyme inhibitors.Journal of Biological Chemistry, 1979
- Stability of some molecular complexes in aqueous mixed solvents. Correlation with solvent surface tensionJournal of the American Chemical Society, 1971