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Studies of Glutathione Transferase P1‐1 Bound to a Platinum(IV)‐Based Anticancer Compound Reveal the Molecular Basis of Its Activation
Author(s) -
Parker Lorien J.,
Italiano Louis C.,
Morton Craig J.,
Hancock Nancy C.,
Ascher David B.,
Aitken Jade B.,
Harris Hugh H.,
Campomanes Pablo,
Rothlisberger Ursula,
De Luca Anastasia,
Lo Bello Mario,
Ang Wee Han,
Dyson Paul J.,
Parker Michael W.
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201100586
Subject(s) - glutathione s transferase , chemistry , glutathione , transferase , platinum , glutathione transferase , platinum compounds , biochemistry , cancer research , enzyme , biology , catalysis
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‐ Pt IV 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.