Currently, no clinically approved therapeutic drugs specifically target dengue virus infections. This study aims to evaluate the potential of antiviral drugs originally developed for other purposes as viable candidates for combating dengue virus. The RNA-elongating NS5-NS3 complex is a critical molecular structure responsible for dengue virus replication. Using the cryo-electron microscopy (Cryo-EM) structures available in the Protein Data Bank and AlphaFold 3 predictions, this study simulated the replication complexes of dengue virus serotypes 1, 2, 3, and 4. The RNA-dependent RNA polymerase (RdRp) domain of the NS5 protein within the NS5-NS3 complex was selected as the molecular docking template. Molecular docking simulations were conducted using AutoDock4. Seven small molecules—AT-9010, RK-0404678, Oseltamivir, Remdesivir, Favipiravir-RTP, Abacavir, and Ribavirin—were assessed for binding affinity by calculating their binding energies, where lower values indicate stronger molecular interactions. Based on published data, antiviral replication assays were conducted for the four dengue virus serotypes. AT-9010 and RK-0404678 were used as benchmarks for antiviral replication efficacy, while Oseltamivir served as the control group. The Mann-Whitney U test was employed to classify the clinical antiviral candidates—Remdesivir, Favipiravir-RTP, Abacavir, and Ribavirin. Results demonstrated that among the four small molecules, Favipiravir-RTP exhibited the highest binding affinity with the RdRp domain of the NS5-NS3 complex across all four dengue virus serotypes. Statistical classification revealed that in five simulated scenarios—including the four virus serotypes and Cryo-EM structural data—Favipiravir-RTP shared three classifications with the benchmark molecule AT-9010. Based on these findings, Favipiravir-RTP, a broad-spectrum antiviral agent, shows potential as a therapeutic option for inhibiting dengue virus replication. However, further clinical trials are necessary to validate their efficacy in humans.
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