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<p>Currently, no approved direct-acting antivirals are available for dengue virus (DENV), highlighting the need for novel therapeutic strategies. The NS3–NS4B interaction is essential for replication complex assembly, making it a promising antiviral target. In this study, we employed a comprehensive in silico workflow to investigate the flavonoid naringenin as a potential inhibitor of the NS3–NS4B interaction in DENV-2. Initially, 3D structures of NS3 and its interacting partners, NS1 and NS5, were retrieved from the PDB. The 3D structure of NS4B and NS2B were generated using homology modeling. Protein–protein docking identified NS3–NS4B as the highest-scoring complex, selected for interface residue analysis. Naringenin docking with NS3 revealed three interface residues (Leu193, His194, Ala197) shared with NS4B binding. Complex stability was evaluated using 50 ns all-atom molecular dynamics simulations. Binding energy profiles, RMSF analysis, and persistent hydrogen bonding supported a stable NS3–naringenin interaction. Further analysis of the NS3 and NS4B mutant (G124A) interaction also showed the involvement of the same three amino acids. Evolutionary conservation analysis using the ConSurf server revealed that the three residues are highly conserved, underscoring their functional importance. The data suggest that naringenin may potentially inhibit the NS3–NS4B interaction, thereby disrupting replication in wild-type and selected mutant strains of DENV-2 but further experimental validation is required.</p>

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Molecular docking and dynamics assessment of naringenin targeting NS3–NS4B interaction in dengue virus (DENV-2)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Sonali Acharya,
  • Raghunath Satpathy

摘要

Currently, no approved direct-acting antivirals are available for dengue virus (DENV), highlighting the need for novel therapeutic strategies. The NS3–NS4B interaction is essential for replication complex assembly, making it a promising antiviral target. In this study, we employed a comprehensive in silico workflow to investigate the flavonoid naringenin as a potential inhibitor of the NS3–NS4B interaction in DENV-2. Initially, 3D structures of NS3 and its interacting partners, NS1 and NS5, were retrieved from the PDB. The 3D structure of NS4B and NS2B were generated using homology modeling. Protein–protein docking identified NS3–NS4B as the highest-scoring complex, selected for interface residue analysis. Naringenin docking with NS3 revealed three interface residues (Leu193, His194, Ala197) shared with NS4B binding. Complex stability was evaluated using 50 ns all-atom molecular dynamics simulations. Binding energy profiles, RMSF analysis, and persistent hydrogen bonding supported a stable NS3–naringenin interaction. Further analysis of the NS3 and NS4B mutant (G124A) interaction also showed the involvement of the same three amino acids. Evolutionary conservation analysis using the ConSurf server revealed that the three residues are highly conserved, underscoring their functional importance. The data suggest that naringenin may potentially inhibit the NS3–NS4B interaction, thereby disrupting replication in wild-type and selected mutant strains of DENV-2 but further experimental validation is required.