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

doi:10.3390/biom13040613

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^*

^*Corresponding author for this work

Turku Bioscience Centre

Research output: Contribution to journal › Article › Scientific › peer-review

5 Citations (Scopus)

103 Downloads (Pure)

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.

Original language	English
Article number	613
Number of pages	15
Journal	Biomolecules
Volume	13
Issue number	4
DOIs	https://doi.org/10.3390/biom13040613
Publication status	Published - 29 Mar 2023
MoE publication type	A1 Journal article-refereed

Funding

ACP thanks Biocenter Finland and Academy of Finland for infrastructure support. We thank Sandrine Le Hello for help during crystallizations. Access to EMBL-Hamburg was provided by iNEXT, project number 653706, funded by the Horizon 2020 program.

Keywords

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

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10.3390/biom13040613

biomolecules-13-00613Final published version, 3.03 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe202402136921

Cite this

@article{c2faa40b55cf4e9e9e513d34521728fc,

title = "Inhibition Analysis and High-Resolution Crystal Structure of Mus musculus Glutathione Transferase P1-1",

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 {\AA} 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.",

keywords = "anticancer drugs, cancer, enzyme inhibition, glutathione transferase, human glutathione transferase P1-1 (hGSTP1-1), multidrug resistance, pesticide, anticancer drugs, Cancer, human glutathione transferase P1-1 (hGSTP1-1), glutathione transferase, enzyme inhibition, multidrug resistance, pesticide",

author = "Oleksii Kupreienko and Fotini Pouliou and Konstantinos Konstandinidis and Irene Axarli and Eleni Douni and Papageorgiou, \{Anastassios C.\} and Labrou, \{Nikolaos E.\}",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

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day = "29",

doi = "10.3390/biom13040613",

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T1 - Inhibition Analysis and High-Resolution Crystal Structure of Mus musculus Glutathione Transferase P1-1

AU - Kupreienko, Oleksii

AU - Pouliou, Fotini

AU - Konstandinidis, Konstantinos

AU - Axarli, Irene

AU - Douni, Eleni

AU - Papageorgiou, Anastassios C.

AU - Labrou, Nikolaos E.

PY - 2023/3/29

Y1 - 2023/3/29

N2 - 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.

AB - 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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KW - cancer

KW - enzyme inhibition

KW - glutathione transferase

KW - human glutathione transferase P1-1 (hGSTP1-1)

KW - multidrug resistance

KW - pesticide

KW - anticancer drugs

KW - Cancer

KW - human glutathione transferase P1-1 (hGSTP1-1)

KW - glutathione transferase

KW - enzyme inhibition

KW - multidrug resistance

KW - pesticide

UR - https://www.scopus.com/pages/publications/85156125067

U2 - 10.3390/biom13040613

DO - 10.3390/biom13040613

M3 - Article

C2 - 37189361

AN - SCOPUS:85156125067

SN - 2218-273X

VL - 13

JO - Biomolecules

JF - Biomolecules

IS - 4

M1 - 613

ER -

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

Abstract

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Keywords

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