A1 Refereed original research article in a scientific journal

Inhibition Analysis and High-Resolution Crystal Structure of Mus musculus Glutathione Transferase P1-1




AuthorsKupreienko Oleksii, Pouliou Fotini, Konstandinidis Konstantinos, Axarli Irene, Douni Eleni, Papageorgiou Anastassios C., Labrou Nikolaos E.

PublisherMDPI

Publication year2023

JournalBiomolecules

Journal name in sourceBIOMOLECULES

Journal acronymBIOMOLECULES

Article number 613

Volume13

Issue4

Number of pages15

eISSN2218-273X

DOIhttps://doi.org/10.3390/biom13040613(external)

Web address https://doi.org/10.3390/biom13040613(external)

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/179811672(external)


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.


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