Structure-guided discovery of submicromolar 1,2,4-triazole–Schiff-base inhibitors of glutathione reductase
International Journal of Biological Macromolecules, cilt.337, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 337
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.ijbiomac.2025.149471
- Dergi Adı: International Journal of Biological Macromolecules
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Compendex, EMBASE, INSPEC, MEDLINE
- Anahtar Kelimeler: 1,2,4-triazole–Schiff base, Antioxidant assays, Boltz-2, Ferroptosis sensitization, Glutathione reductase, Molecular dynamics simulations
- Karadeniz Teknik Üniversitesi Adresli: Evet
Özet
Glutathione 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 μM), significantly surpassing quercetin (IC50 = 214.5 ± 18.5 μM). 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 deep-learning–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 AUR-517. 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.