Structure-guided discovery of submicromolar 1,2,4-triazole-Schiff-base inhibitors of glutathione reductase

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dc.authorid0000-0002-9018-7264
dc.authorid0000-0003-3317-9505
dc.contributor.authorManap, Sevda
dc.contributor.authorAkar, Hande
dc.contributor.authorMedetalibeyoglu, Hilal
dc.contributor.authorAtalay, Abdurrahman
dc.contributor.authorCan, Zehra
dc.contributor.authorKara, Yakup
dc.contributor.authorOrtaakarsu, Ahmet Bugra
dc.date.accessioned2026-02-28T12:17:49Z
dc.date.available2026-02-28T12:17:49Z
dc.date.issued2026
dc.departmentBayburt Üniversitesi
dc.description.abstractGlutathione reductase (GR) plays a crucial role in maintaining cellular redox balance and is a promising target for ferroptosis-based cancer therapies. In this study, we report the design, synthesis, and comprehensive evaluation of a novel series of 1,2,4-triazole-Schiff base succinate derivatives (AUR-514-518) as potent GR inhibitors. In vitro Mannervik assays revealed vigorous submicromolar inhibitory activity, with AUR-517 emerging as the most effective (IC50 = 0.471 +/- 0.032 mu M), significantly surpassing quercetin (IC50 = 214.5 +/- 18.5 mu M). Antioxidant profiling revealed negligible radical scavenging activity; however, modest CUPRAC responses suggest a target-specific mechanism. To elucidate the molecular determinants of inhibition, we employed deeplearning-assisted protein-ligand affinity predictions, molecular dynamics simulations, MM/GBSA free-energy calculations, and dimensional reduction analyses. These computational studies revealed dual binding modes at both the catalytic site and dimer interface, with AUR-517 forming stable interactions with key catalytic residues, consistent with experimental potency rankings. The RMSD/RMSF profiles indicated enhanced conformational stability of GR-ligand complexes, while binding energy landscapes underscored the superior stability of AUR517. Consequently, these findings establish the AUR series as a new class of structurally validated GR inhibitors, with AUR-517 representing a lead scaffold for the rational development of ferroptosis-sensitizing agents with translational potential in oncology.
dc.description.sponsorshipAurealcraft Therapeutics; Scientific Research Project Fund of Kafkas University [2018-FM-46]; TUBITAK ULAKBIM's High Performance and Grid Computing Center
dc.description.sponsorshipAurealcraft Therapeutics supports this research under the project AUREXIS (ARF-500), which focuses on ferroptosis-potent research. Aurealcraft Therapeutics and collaborating academic partners provided high-performance computing and scientific infrastructure. In addition, this research is supported by the Scientific Research Project Fund of Kafkas University under project number 2018-FM-46. It was also supported by TUBITAK ULAKBIM's High Performance and Grid Computing Center (TRUBA resources).
dc.identifier.doi10.1016/j.ijbiomac.2025.149471
dc.identifier.issn0141-8130
dc.identifier.issn1879-0003
dc.identifier.pmid41349751
dc.identifier.scopus2-s2.0-105024432606
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.ijbiomac.2025.149471
dc.identifier.urihttps://hdl.handle.net/20.500.12403/5996
dc.identifier.volume337
dc.identifier.wosWOS:001641343000001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier
dc.relation.ispartofInternational Journal of Biological Macromolecules
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WoS_20260218
dc.subject4-triazole-Schiff base
dc.subjectGlutathione reductase
dc.subjectFerroptosis sensitization
dc.subjectMolecular dynamics simulations
dc.subjectAntioxidant assays
dc.subjectBoltz-2
dc.titleStructure-guided discovery of submicromolar 1,2,4-triazole-Schiff-base inhibitors of glutathione reductase
dc.typeArticle

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