Maulana, Saipul and Wahyuni, Tutik Sri and Zubair, Muhammad Sulaiman and Musnina, Wa Ode Sitti and Jamaluddin Mahmud, - and Yuyun, Yonelian (2026) Targeting Multiple Hepatitis C Virus Proteins with Lignans from the Piper Genus: A Molecular Docking and Dynamics Study. Tropical Journal of Natural Product Research, 10 (2). 7087 - 7096.

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Abstract

Hepatitis is an inflammatory liver disease primarly caused by viral infections, including hepatitis A, B, C, D, and E viruses. Among these, hepatitis C virus (HCV) is of particular concern due to its high rate of chronic infection, which often progresses to cirrhosis and hepatocellular carcinoma. Despite the availability of direct-acting antivirals (DAAs), high treatment costs and the absence of a vaccine remain major barriers to global HCV eradication. This study aimed to identify potential anti-HCV compounds from lignan metabolites of the Piper genus. Molecular docking followed by molecular dynamics (MD) simulations was used to evaluate evaluate ligand binding to multiple HCV protein targets. Screening of the lignan metabolites revealed three 'hit' compounds compared to the reference drug on the Hepatitis C virus non-structural protein 3 (NS3), Hepatitis C virus non-structural protein 5B (NS5B), Hepatitis C virus envelope glycoprotein E1 (E1), and Hepatitis C virus envelope glycoprotein E2 (E2) receptors: Piperbonamide A (-57.20 kcal/mol), Dipiperamide D (-56.97 &-72.87 kcal/mol), and Ferrudiol (-70.77 kcal/mol). Subsequently, MD simulations revealed the Ferrudiol-E2 complex maintained consistently low root mean square deviation (RMSD) values (<3 à ) over 100 ns simulation times, indicating a stable and persistent binding interaction. In contrast, Piperbonamide A-NS3 and Dipiperamide D-NS5B exhibited moderate to reduced stability, while Dipiperamide D-E1 showed pronounced instability with large RMSD fluctuations. Furthermore, absorption, distribution, metabolism, and excretion (ADME) predictions showed Ferrudiol possesses recommended favorable physicochemical properties. This study successfully identifies Ferrudiol as a potential lignan candidate warranting further development as an anti-HCV agent. © 2026 the authors.

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