| Yazarlar (5) |
Cüneyt Türkeş
Erzincan Binali Yıldırım Üniversitesi, Türkiye |
|
Nebih Lolak
Adıyaman Üniversitesi, Türkiye |
Doç. Dr. Hatice Esra DURAN
Kafkas Üniversitesi, Türkiye |
|
Gönül Yapar
İstanbul Teknik Üniversitesi, Türkiye |
|
Süleyman Akocak
Adıyaman Üniversitesi, Türkiye |
| Özet |
| The conformational and kinetic intricacies of enzyme-ligand interactions are critical for understanding molecular mechanisms underlying metabolic and neurodegenerative pathologies. Herein, we report a rationally designed series of ureido-benzenesulfonamides as dual-acting nanomolar inhibitors targeting aldose reductase (ALR2) and cholinesterases (AChE and BChE). Spectrophotometric inhibition assays revealed that compound 3SA-a displayed exceptional ALR2 affinity (K = 7.00 ± 0.68 nM), surpassing epalrestat by over 30-fold. Likewise, 3SA-f selectively inhibited BChE with a K of 24.20 ± 2.26 nM, outperforming tacrine by a factor of 7.8. Molecular docking simulations highlighted distinct dynamic binding modes: 3SA-a engaged ALR2's catalytic cleft through a hydrogen bond with Tyr48 and water-bridged interactions, whereas 3SA-f leveraged π-π stacking and halogen bonding within BChE's extended acyl pocket. These binding orientations were consistent with SAR findings, where meta-sulfonamide placement and halogen substitution optimized selectivity and conformational complementarity. Complementary in silico ADME-Tox predictions confirmed the drug-like nature of all compounds (0 Lipinski/PAINS violations), moderate oral permeability (QPPCaco: 79-85 nm/s), and low CNS exposure (CNS score = -2), aligning with a peripheral mechanism of action. Collectively, this study provides a detailed structural and dynamic framework for dual-target enzyme inhibition, offering a tunable scaffold for future therapeutics targeting the ALR2-ChE axis. |
| Anahtar Kelimeler |
| Ureido-benzenesulfonamides | Aldose reductase | Cholinesterase inhibition | Molecular docking | Structure-activity relationship |
| Makale Türü | Özgün Makale |
| Makale Alt Türü | SSCI, AHCI, SCI, SCI-Exp dergilerinde yayınlanan tam makale |
| Dergi Adı | Archives of Biochemistry and Biophysics |
| Dergi ISSN | 0003-9861 Wos Dergi Scopus Dergi |
| Dergi Tarandığı Indeksler | SCI-Expanded |
| Dergi Grubu | Q1 |
| Makale Dili | Türkçe |
| Basım Tarihi | 11-2025 |
| Cilt No | 773 |
| Doi Numarası | 10.1016/j.abb.2025.110594 |
| Makale Linki | https://doi.org/10.1016/j.abb.2025.110594 |
| Atıf Sayıları |
