Computational Evaluation of Bunium brachyactis‐Derived Compounds as Inhibitors of DENV3 NS5 RdRp: ADMET, DFT, Docking, and Dynamics Insights

Dengue virus (DENV), transmitted primarily by Aedes aegypti and Aedes albopictus , remains a major global health concern due to the absence of effective antiviral therapies. The RNA‐dependent RNA polymerase (NS5 RdRp) is a validated therapeutic target, given its essential role in viral replication and lack of a human homolog. In this study, seventy phytochemicals from Bunium brachyactis were computationally screened to identify potential DENV3 NS5 RdRp inhibitors. The workflow combined molecular docking, ADMET profiling, density functional theory (DFT) at the B3LYP/6–31G(d,p) level, molecular dynamics (MD) simulations, MM‐GBSA free energy calculations, and free energy landscape (FEL) analysis. Docking revealed that flavonoids and coumarins displayed stronger binding affinities than the reference ligand (B5C). Notably, Luteolin, Flavone, and Scopoletin consistently emerged as top candidates with favorable docking scores and drug‐like pharmacokinetic features. MD simulations confirmed the structural stability of their complexes with RdRp, supported by RMSD, RMSF, Rg, SASA, and hydrogen bonding analyses. DFT results indicated lower HOMO–LUMO gaps and higher softness, suggesting enhanced charge transfer potential. MM‐GBSA and FEL analyses further validated stable binding in the catalytic pocket. Overall, this study highlights B. brachyactis phytochemicals, particularly Luteolin, Flavone, and Scopoletin, as promising scaffolds for dengue antiviral development, warranting further experimental validation.