In Silico Analysis, Biological Activity, and ADME Profiling of Flavonoid Compounds Targeting RNA-Dependent RNA Polymerase of DENV-3

https://doi.org/10.22146/ijc.108797

Siti Zainatun Wasilah(1), Tri Wibawa(2*), Nastiti Wijayanti(3)

(1) Doctoral Program in Medical and Health Sciences, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; Medical Laboratory Technology, Poltekkes Kemenkes Yogyakarta, Jl. Ngadinegaran MJ III/62, Yogyakarta 55141, Indonesia
(2) Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada Sekip Utara, Yogyakarta 55281, Indonesia
(3) Laboratory of Animal Physiology, Faculty of Biology, Universitas Gadjah Mada, Jl. Teknika Selatan, Sekip Utara, Yogyakarta 55281, Indonesia
(*) Corresponding Author

Abstract


Dengue virus (DENV) remains a global health challenge. DENV-3 is the most virulent of the four dengue virus serotypes, requiring the identification of new inhibitors against RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral replication. This study evaluated the inhibitory potential of flavonoids, including quercetin, fisetin, myricetin, daidzein, and ribavirin. Molecular docking revealed binding energies of −8.0, −7.4, −7.3, and −7.4 kcal/mol for quercetin, fisetin, myricetin, and daidzein, respectively, exceeding those of ribavirin as a control (−5.6 kcal/mol). These ligands exhibit strong interactions with active site residues, including hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations of 100 ns confirmed a stable protein-ligand complex, with quercetin showing a stable RMSD and RoG values compared to the control, indicating good binding stability. SASA and hydrogen bond analysis support the stability of quercetin interactions. Pharmacokinetic evaluation shows that four ligands comply with Lipinski's rules of five, supporting their potential as drug candidates. These findings highlight the potential of quercetin, fisetin, myricetin, and daidzein as DENV-3 RdRp inhibitors, with quercetin as the most effective, with the lowest binding energy and inhibition constant. Experimental validation is needed to explore the potential antiviral effects of DENV.


Keywords


flavonoids; DENV-3; molecular docking; molecular dynamics; quercetin

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DOI: https://doi.org/10.22146/ijc.108797

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