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Inhibition Analysis and High-Resolution Crystal Structure of Mus musculus Glutathione Transferase P1-1
Oleksii Kupreienko1, Fotini Pouliou1, Konstantinos Konstandinidis1
1Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, 11855 Athens, Greece.
Abstract:
Multidrug resistance is a significant barrier that makes anticancer therapies less effective. Glutathione transferases (GSTs) are involved in multidrug resistance mechanisms and play a significant part in the metabolism of alkylating anticancer drugs. The purpose of this study was to screen and select a lead compound with high inhibitory potency against the isoenzyme GSTP1-1 from Mus musculus (MmGSTP1-1). The lead compound was selected following the screening of a library of currently approved and registered pesticides that belong to different chemical classes. The results showed that the fungicide iprodione [3-(3,5-dichlorophenyl)-2,4-dioxo-N-propan-2-ylimidazolidine-1-carboxamide] exhibited the highest inhibition potency (ΙC50 = 11.3 ± 0.5 μΜ) towards MmGSTP1-1. Kinetics analysis revealed that iprodione functions as a mixed-type inhibitor towards glutathione (GSH) and non-competitive inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). X-ray crystallography was used to determine the crystal structure of MmGSTP1-1 at 1.28 Å resolution as a complex with S-(p-nitrobenzyl)glutathione (Nb-GSH). The crystal structure was used to map the ligand-binding site of MmGSTP1-1 and to provide structural data of the interaction of the enzyme with iprodione using molecular docking. The results of this study shed light on the inhibition mechanism of MmGSTP1-1 and provide a new compound as a potential lead structure for future drug/inhibitor development.
Insights
Researchers identified the pesticide iprodione as a potent inhibitor of glutathione transferase P1-1 (GSTP1-1), an enzyme linked to multidrug resistance in cancer. This finding offers a potential new lead compound for developing anticancer drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) significantly reduces anticancer therapy efficacy.
- Glutathione transferases (GSTs) are key players in MDR and the metabolism of alkylating anticancer drugs.
Purpose of the Study:
- To screen for and identify a lead compound with high inhibitory activity against the mouse isoenzyme GSTP1-1 (MmGSTP1-1).
Main Methods:
- Screening of a pesticide library against MmGSTP1-1.
- Enzyme kinetics analysis.
- X-ray crystallography of MmGSTP1-1-ligand complex.
- Molecular docking studies.
Main Results:
- The fungicide iprodione demonstrated the highest inhibitory potency against MmGSTP1-1 (IC50 = 11.3 ± 0.5 μM).
- Iprodione acts as a mixed-type inhibitor for glutathione (GSH) and a non-competitive inhibitor for CDNB.
- Crystal structure of MmGSTP1-1 complexed with S-(p-nitrobenzyl)glutathione (Nb-GSH) was determined at 1.28 Å resolution.
Conclusions:
- Iprodione is a potent inhibitor of MmGSTP1-1.
- Structural data elucidates the inhibition mechanism and provides a basis for designing novel anticancer agents.
- Iprodione represents a promising lead structure for future drug development targeting GSTP1-1.
