Evidence mapPaperPMID 39954068Full record

ArticleNaunyn-Schmiedeberg's archives of pharmacology2025

Investigation of the inhibitory effects of the telomere-targeted compounds on glutathione S-transferase P1.

Mehmet Ozcan, Ayse Burus, Ilgen Mender, Z Gunnur Dikmen, Sergei M Gryaznov, Turgut Bastug, Yasemin Bayazit

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Article in Naunyn-Schmiedeberg's archives of pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

7 authors.

Mehmet OzcanDepartment of Medical Biochemistry, Faculty of Medicine, Zonguldak Bulent Ecevit University, Zonguldak, Turkey.
Ayse BurusDepartment of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Ilgen MenderMAIA Biotechnology, Inc., Chicago, IL, 60606, USA.
Z Gunnur DikmenDepartment of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Sergei M GryaznovMAIA Biotechnology, Inc., Chicago, IL, 60606, USA.
Turgut BastugDepartment of Biophysics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Yasemin BayazitDepartment of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey. yaseminb@hacettepe.edu.tr.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Glutathione S-transferase P1 (GSTP1) plays a significant role in cancer progression and chemotherapy resistance, with its overexpression diminishing chemotherapeutic efficacy across various tumor types. This study evaluates the inhibitory effects of 6-thio-2'-deoxyguanosine (6-thio-dG) and its dimeric form (6-thio-2'-dG-Dimer) on GSTP1. Enzyme inhibition assays with recombinant human GSTP1, kinetic analysis, molecular docking, and molecular dynamic simulations were employed. Enzymatic assays were performed in 0.1 M phosphate buffer (pH 6.5) at 30 °C, containing 1 mM EDTA, 1 mM GSH, and 1 mM CDNB. The compounds 6-thio-dG and its dimer were dissolved in 2.5% DMSO for the experiments. The IC₅₀ values indicated that the dimer exhibited a higher potency (IC₅₀: 0.339 μM) than the monomer (IC₅₀: 15.14 μM). Kinetic analysis revealed noncompetitive inhibition with glutathione (Ki: 12.26 μM) and mixed inhibition with CDNB (Ki: 11.41 μM) for the monomer, whereas the dimer showed mixed inhibition with glutathione (Ki: 0.972 μM) and competitive inhibition with CDNB (Ki: 0.723 μM). Molecular docking confirmed the higher binding affinity of the dimer (binding energy: - 7.9 kcal/mol, Ki: 1.595 μM) compared to the monomer (binding energy: - 6.2 kcal/mol, Ki: 28.21 μM). The dimer form of 6-thio-dG shows strong potential to enhance chemotherapeutic efficacy by effectively inhibiting GSTP1 and overcoming drug resistance. Its superior inhibitory properties make it a valuable candidate for targeted cancer therapies.

Indexed as

Enzyme InhibitorsGlutathione S-Transferase piTelomereHumansKineticsMolecular Docking SimulationMolecular Dynamics SimulationRecombinant ProteinsEnzyme InhibitorsGlutathione S-Transferase piGSTP1 protein, humanRecombinant Proteins6-thio-2′-deoxyguanosinDrug resistanceGlutathione S-transferase P1Telomere-targeted drugs

Identifiers

PMID39954068
PMCPMC12350525

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.