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

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

*Korresponderande författare för detta arbete

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

2 Citeringar (Scopus)
13 Nedladdningar (Pure)

Sammanfattning

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.
OriginalspråkEngelska
Artikelnummer613
Antal sidor15
TidskriftBiomolecules
Volym13
Nummer4
DOI
StatusPublicerad - 29 mars 2023
MoE-publikationstypA1 Tidskriftsartikel-refererad

Nyckelord

  • anticancer drugs
  • Cancer
  • human glutathione transferase P1-1 (hGSTP1-1)
  • glutathione transferase
  • enzyme inhibition
  • multidrug resistance
  • pesticide

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