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

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 nitrilesubstituted 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 (Delta G = -7.18 to -9.58 kcal/mol), with compound 5 exhibiting the strongest interaction (Delta G = -9.58 kcal/mol, theoretical IC50 = 94.64 nM), outperforming the reference ligand SAH (Delta G = -7.18 kcal/mol). ADME profiling demonstrated favorable drug-likeness, acceptable solubility, bloodbrain 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.