Bivalent inhibitors of glutathione S-transferase: the effect of spacer length on isozyme selectivity.

Article Details

Citation

Maeda DY, Mahajan SS, Atkins WM, Zebala JA

Bivalent inhibitors of glutathione S-transferase: the effect of spacer length on isozyme selectivity.

Bioorg Med Chem Lett. 2006 Jul 15;16(14):3780-3. Epub 2006 May 3.

PubMed ID
16675217 [ View in PubMed
]
Abstract

Glutathione S-transferases (GSTs) are cytosolic enzymes that catalyze the conjugation of glutathione with a variety of exogenous and endogenous electrophiles. High affinity, isozyme-specific inhibitors of GST are required for use as pharmacological tools as well as potential therapeutics. The design of selective inhibitors is hindered due to the broad substrate binding capabilities of the GST enzymes. GSTs are dimeric enzymes, and therefore offer a unique discriminator for achieving inhibitor selectivity: the distance between binding sites on each monomer unit as a function of its quaternary organization. Bivalent analogs of the non-selective GST inhibitor ethacrynic acid were prepared, and selectivity for the GST A1-1 isozyme over GST P1-1 (IC50 values of 13.7 vs 1022 nM, respectively) was achieved through the optimization of the spacer length between the ethacrynic acid ligand domains.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Etacrynic acidGlutathione S-transferase PIC 50 (nM)4000N/AN/ADetails