Flavonoid Scaffolds as Promising Antiviral Leads Against Varicella Zoster Virus (Chickenpox): A Structure-Guided Virtual Screening Study

Abstract

Purpose: Varicella-Zoster Virus (VZV) remains a significant global health concern, particularly among immunocompromised and vulnerable populations. Limitations associated with existing antiviral therapies, including adverse effects and emerging resistance, necessitate the identification of safer and more effective alternatives. This study employed a structure-guided in-silico strategy to identify flavonoid-based inhibitors targeting VZV thymidine kinase (VZV-TK). Methods: A curated library of 264 flavonoids was subjected to hierarchical molecular docking using the Schrödinger suite, followed by binding free energy estimation via the MM-GBSA approach. Pharmacokinetic and toxicity properties were evaluated through ADMET profiling. The most promising ligand–protein complexes were further assessed using 100 ns all-atom molecular dynamics simulations to examine binding stability and conformational behavior. Results: Several flavonoids demonstrated strong binding affinity toward VZV-TK. Neohesperidin dihydrochalcone exhibited the most favorable binding free energy, indicating high thermodynamic stability, while naringin dihydrochalcone and myricitrin showed docking scores comparable to the co-crystallized reference ligand. Molecular dynamics analyses identified myricitrin as the most dynamically stable inhibitor, characterized by low backbone RMSD, persistent hydrogen-bonding interactions, and preserved protein compactness. ADMET predictions indicated acceptable physicochemical properties and low carcinogenicity risk for the lead compounds. Conclusion: The integrated computational analyses highlight flavonoid scaffolds, particularly myricitrin, neohesperidin dihydrochalcone, and naringin dihydrochalcone, as promising VZV-TK inhibitors. These findings provide a strong rationale for further experimental validation and support the development of plant-derived antivirals for Varicella-Zoster Virus infection.