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<p>The dengue virus has developed an effective replication mechanism that enables rapid viral replication in human hosts. The use of a molecular bottleneck offers an ideal approach for antiviral intervention, especially when no clinically authorized antivirals are available against dengue. The replication process is challenging due to functional redundancy. One of the core antiviral targets is the viral RNA-dependent RNA polymerase (RdRp), a conserved and essential component of the DENV replication machinery with no mammalian homolog, which represents a promising target for antiviral intervention. This study employed a multi-tiered drug repurposing approach integrating computational screening, high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) molecular docking of SelleckChem FDA-approved &amp; Passed Phase I Drug Library compounds against the DENV RdRp (PDB:5K5M), followed by 200 ns molecular dynamics (MD) simulations, free binding energy analysis, free energy landscape (FEL) analysis, and in vitro antiviral validation. From the screening cascade, Proanthocyanidin and Stachyose were identified as lead candidates with Glide XP docking scores of -11.34 and − 13.08&#xa0;kcal/mol and Molecular Mechanics/Generated Born Surface Area (MM-GBSA) binding free energies of -52.35 ± 5.29&#xa0;kcal/mol, respectively. These lead candidates established stable interactions with important catalytic and regulatory residues, including Arg<sup>729</sup>, Thr<sup>794</sup>, Ser<sup>796</sup>, Asp<sup>664</sup>, and Tyr<sup>766,</sup> indicating their ability to disrupt key polymerase activity. The stability of the candidates was further confirmed by Molecular dynamics simulations based on the minimal variations of RMSD and compactness of the protein compared with the lead structures, which collectively indicated their compatibility with the polymerase allosteric site. Critically, in vitro assays conducted on DENV infected cells confirmed the Proanthocyanidin exhibited potent dose-dependent antiviral activity with IC<sub>50</sub> values of 4.26–7.07 µM across DENV serotypes 1–4, with CC<sub>50</sub> &gt;100 µM and selectivity indices &gt; 14, indicating a favorable therapeutic window. These findings identify Proanthocyanidin as a promising RdRp-targeting antiviral candidate and demonstrate the value of integrating computational and experimental approaches for dengue drug discovery.</p> Graphical Abstract <p></p>

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Precision repurposing of clinically characterized molecules targeting dengue virus RNA-dependent RNA polymerase: an in silico identification and in vitro validation

  • 期刊论文

  • 发表日期：

    2026年7月16日

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  • Hrithika Panday,
  • Babita Bohra,
  • Rahul Shukla,
  • Vivek Dhar Dwivedi,
  • Abhimanyu Kumar Jha

摘要

The dengue virus has developed an effective replication mechanism that enables rapid viral replication in human hosts. The use of a molecular bottleneck offers an ideal approach for antiviral intervention, especially when no clinically authorized antivirals are available against dengue. The replication process is challenging due to functional redundancy. One of the core antiviral targets is the viral RNA-dependent RNA polymerase (RdRp), a conserved and essential component of the DENV replication machinery with no mammalian homolog, which represents a promising target for antiviral intervention. This study employed a multi-tiered drug repurposing approach integrating computational screening, high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) molecular docking of SelleckChem FDA-approved & Passed Phase I Drug Library compounds against the DENV RdRp (PDB:5K5M), followed by 200 ns molecular dynamics (MD) simulations, free binding energy analysis, free energy landscape (FEL) analysis, and in vitro antiviral validation. From the screening cascade, Proanthocyanidin and Stachyose were identified as lead candidates with Glide XP docking scores of -11.34 and − 13.08 kcal/mol and Molecular Mechanics/Generated Born Surface Area (MM-GBSA) binding free energies of -52.35 ± 5.29 kcal/mol, respectively. These lead candidates established stable interactions with important catalytic and regulatory residues, including Arg729, Thr794, Ser796, Asp664, and Tyr766, indicating their ability to disrupt key polymerase activity. The stability of the candidates was further confirmed by Molecular dynamics simulations based on the minimal variations of RMSD and compactness of the protein compared with the lead structures, which collectively indicated their compatibility with the polymerase allosteric site. Critically, in vitro assays conducted on DENV infected cells confirmed the Proanthocyanidin exhibited potent dose-dependent antiviral activity with IC50 values of 4.26–7.07 µM across DENV serotypes 1–4, with CC50 >100 µM and selectivity indices > 14, indicating a favorable therapeutic window. These findings identify Proanthocyanidin as a promising RdRp-targeting antiviral candidate and demonstrate the value of integrating computational and experimental approaches for dengue drug discovery.

Graphical Abstract