Conformational dynamics and binding free energy analyses unveil a stable flavonoid inhibitor of dengue virus NS5 polymerase

The persistent global spread of Dengue Virus (DENV) necessitates the identification of novel Antiviral therapeutics. The RNA-dependent RNA polymerase (RdRp) domain of the non-structural protein 5 (NS5) is a validated target for therapy due to its critical roles in viral genome replication. In this study, we used a structure-guided virtual screening approach to identify potent phytochemical inhibitors of DENV RdRp from the Plant Secondary Compound Database (PSC-db) by focusing on 326 Flavonoids. Following drug-likeness filtering and hierarchical docking with MM-GBSA analysis, five top candidates were identified, with PSCdb01560 emerging as the most promising. Subsequent molecular dynamics simulations over 500 ns revealed PSCdb01560's exceptional binding stability, characterised by low protein-ligand RMSD and sustained binding stability. Free energy landscape analysis demonstrated its occupation of deep, well-defined conformational basins. At the same time, post-MD MM-GBSA yielded a binding free energy of -91.65 kcal/mol-outperforming the reference compound. Structural superimposition confirmed strong conformational fidelity between docked and minimum-energy poses (RMSD 1.68 Å). Together, our approach points toward PSCdb01560 as the putative inhibitor molecule that outperforms existing flavonoid leads in thermodynamic and kinetic descriptors. The results thus provide the avenue for experimental validation, such as enzymatic and Antiviral screens, in hopes of turning these in silico observations into viable therapeutic development for dengue.

Dengue virus; Drug discovery; Natural compounds; PSC-db; RdRp.