| Yazarlar (10) |
Sevda Manap
Kafkas Üniversitesi, Türkiye |
|
Hande Akar
Gazi Üniversitesi, Türkiye |
|
Hilal Medetalibeyoğlu
Kafkas Üniversitesi, Türkiye |
|
Abdurrahman Atalay
Avrasya Üniversitesi, Türkiye |
|
Zehra Can
Bayburt Üniversitesi, Türkiye |
|
Yakup Kara
Karadeniz Technical University, Türkiye |
|
Muzaffer Alkan
Kafkas Üniversitesi, Türkiye |
Doç. Dr. Murat BEYTUR
Kafkas Üniversitesi, Türkiye |
|
Haydar Yüksek
Kafkas Üniversitesi, Türkiye |
|
Ahmet Buğra Ortaakarsu
Gazi Üniversitesi, Türkiye |
| 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. |
| Anahtar Kelimeler |
| 1,2,4-triazole–Schiff base | Antioxidant assays | Boltz-2 | Ferroptosis sensitization | Glutathione reductase | Molecular dynamics simulations |
| Makale Türü | Özgün Makale |
| Makale Alt Türü | SSCI, AHCI, SCI, SCI-Exp dergilerinde yayınlanan tam makale |
| Dergi Adı | International Journal of Biological Macromolecules |
| Dergi ISSN | 0141-8130 Wos Dergi Scopus Dergi |
| Dergi Grubu | Q1 |
| Makale Dili | İngilizce |
| Basım Tarihi | 01-2026 |
| Cilt No | 337 |
| Sayı | 1 |
| DOI Numarası | 10.1016/j.ijbiomac.2025.149471 |
| Atıf Sayıları |
