DOI: 10.12688/f1000research.187760.1 ISSN: 2046-1402

Identification of Potent Anti-Dengue Activity from Indonesia Plant Extracts: In Vitro and In Silico Analyses

Fidya Miltaputri, Dimas Fandi Praditya, Kazumi Haga, Syamsu Nur, Roshamur Cahyan Forestrania, Achmad Afdal Razzaq Fakhrez, Kezia Adinda Larasati Weru, Najmah Tamam Aldzikra, Donna Maretta Ariestanti, Berna Elya, Danang Waluyo, Meng Ling Moi, Juliann Nzembi Makau, Ken Watanabe, Ratika Rahmasari
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Abstract* Background Dengue virus remains a major global health concern, necessitating the need to identify novel antiviral agents. This study aimed to evaluate the antiviral activity of twelve Indonesian medicinal plant ethanolic extract against Dengue virus and identify potential bioactive compounds. Method The antiviral activity was assessed by plaque formation, real-time polymerase chain reaction, time-of- addition, and immunofluorescence assay. The phytochemical profile of the most active extract was characterized by liquid chromatography–high resolution mass spectrometry. The activity of identified compounds against Dengue envelope protein and their absorption, distribution, metabolism, and excretion properties were evaluated in silico using molecular docking and SwissADME. Result The three plant ethanolic extracts showed potential anti-Dengue virus activity with 50% inhibitory concentrations of 7.8 μg/mL for Phyllanthus niruri , 15.6 μg/mL for Syzygium polyanthum , and 22.6 μg/mL for Uncaria gambir. Phyllanthus niruri extract exhibited pronounced inhibitory activity in all stages of infection compared to others. Phytochemical profiling of Phyllanthus niruri extract, identified various compounds, including flavonoids, amino acid derivatives, and alkaloid-like structures. Molecular docking against Dengue virus envelope proteins (PDB ID: 1OKE and 4GSX) suggested that 1-[4-({4-[(3,5-Dimethyladamantan-1-yl)amino]butyl}amino)butyl] guanidine, (2 S )-3-Methyl-2-({[(3 S ,4 S ,5 R )-2,3,4-trihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]methyl}amino) butanoic acid, and N -cyclooctylurea, exhibited stronger predicted binding to the fusion-activating transition state structure of the envelope glycoprotein (PDB ID: 1OKE) compared to the native ligand. In contrast, these compounds showed lower predicted binding affinity toward late-stage fusion intermediate structure (PDB ID: 4GSX). Absorption, distribution, metabolism, and excretion prediction indicated that several compounds had favorable drug-likeness and pharmacokinetic properties, whereas highly polar flavonoids showed lower predicted oral absorption and membrane permeability. Conclusion This study revealed that Phyllanthus niruri , Syzygium polyanthum , and Uncaria gambir ethanolic extract exhibit inhibitory activity against Dengue virus, with Phyllanthus niruri extract showing strongest activity among tested extract. The combined experimental and computational investigation supported Phyllanthus niruri extract as the potential source to be developed as anti-Dengue agents.

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