High-throughput in vitro screening and in silico analysis for Zika virus inhibitor identification

Zika Virus (ZIKV) is a mosquito-borne virus that can cause serious health problems, including birth defects and neurological complications. Unfortunately, there are no antivirals currently approved for its treatments. In this study, we tested a library of 348 chemical compounds to find potential candidates that could block ZIKV infection. Seven compounds showed strong antiviral activity in laboratory experiments. Among them, Cephalotaxine, Docusate Sodium, and Saikosaponin B2 were the most effective. However, Docusate Sodium may pose safety risks at higher doses, and Saikosaponin B2 has poor solubility, which could limit its use as a drug. To better understand how these compounds work, molecular docking was employed to predict interactions between the active compounds and two important ZIKV proteins: NS5 and the NS2B-NS3 protease complex. The docking results supported the in vitro findings, revealing strong binding affinities, particularly for Saikosaponin B2. Molecular dynamics simulations confirmed stable binding of Saikosaponin B2 and Aloperine to NS5, with Saikosaponin B2 showing greater stability and consistent interactions. Drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis indicated that while some compounds possess favorable pharmacokinetic properties, others may require structural optimization. Overall, this study identifies several promising lead compounds for further preclinical development and highlights the utility of integrating in vitro screening with computational modeling to accelerate antiviral drug discovery against ZIKV.