In silico investigation of tetrazole and oxadiazole compounds as inhibitors of the dengue virus NS5 protein: Synthesis, DFT, ADME and molecular docking analysis

Demirci T., Badreddin Musatat A., KAYA M. O., Arslan M.

Chemico-Biological Interactions, cilt.418, 2025 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 418
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.cbi.2025.111608
  • Dergi Adı: Chemico-Biological Interactions
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, Veterinary Science Database
  • Anahtar Kelimeler: 1,4-Dihydropyridine, ADME, Dengue virus NS5, DFT, Molecular docking, Oxadiazole, Tetrazole
  • Kocaeli Üniversitesi Adresli: Evet

Özet

This study investigates the therapeutic potential of novel tetrazole and oxadiazole derivatives targeting the Dengue virus NS5 protein through an integrated computational and experimental approach. A series of nitrile-substituted 1,4-dihydropyridine (1,4DHPs) derivatives were synthesized and converted into tetrazole and 1,3,4-oxadiazole analogs using established protocols. Structural characterization was performed via NMR, FT-IR, and elemental analysis. Molecular docking studies against the NS5 protein (PDB ID: 6KR2) revealed superior binding affinities for several compounds (ΔG = −7.18 to −9.58 kcal/mol), with compound 5 exhibiting the strongest interaction (ΔG = −9.58 kcal/mol, theoretical IC50 = 94.64 nM), outperforming the reference ligand SAH (ΔG = −7.18 kcal/mol). ADME profiling demonstrated favorable drug-likeness, acceptable solubility, blood-brain barrier penetration, and CYP450 metabolic stability. DFT analyses elucidated electronic properties, including HOMO-LUMO gaps (2.72–4.80 eV) and electrophilicity indices (13.5–23.6 eV), correlating with observed bioactivity. Toxicity predictions identified compound-specific liabilities requiring optimization. These findings highlight the promise of tetrazole-oxadiazole hybrids as potent NS5 inhibitors, warranting further preclinical validation for Dengue therapeutic development.