Studies of Glutathione Transferase P1‐1 Bound to a Platinum(IV)‐Based Anticancer Compound Reveal the Molecular Basis of Its Activation
- 16 June 2011
- journal article
- research article
- Published by Wiley in Chemistry – A European Journal
- Vol. 17 (28), 7806-7816
- https://doi.org/10.1002/chem.201100586
Abstract
Platinum‐based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S‐transferase (GST P1‐1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA‐CPT), a trans‐PtIV carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA‐CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug–protein interactions between EA‐CPT and GST P1‐1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA‐CPT preferentially docks at the dimer interface at GST P1‐1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H‐sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.Keywords
This publication has 46 references indexed in Scilit:
- The resurgence of platinum-based cancer chemotherapyNature Reviews Cancer, 2007
- Quickstep: Fast and accurate density functional calculations using a mixed Gaussian and plane waves approachComputer Physics Communications, 2005
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculationsJournal of Computational Chemistry, 2003
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa Crystallographica Section D-Biological Crystallography, 1997
- A Molecular Mechanics AMBER-Type Force Field for Modeling Platinum Complexes of Guanine DerivativesInorganic Chemistry, 1994
- The CCP4 suite: programs for protein crystallographyActa Crystallographica Section D-Biological Crystallography, 1994
- Structure and function of glutathione S-transferasesBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1994
- Application of RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvationJournal of the American Chemical Society, 1993
- Interactions of glutathione S-transferase-π with ethacrynic acid and its glutathione conjugateBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1993