Dual Mechanisms of Apigenin and Luteolin Against Dengue Virus Serotype 2: Allosteric Inhibition of NS2B/NS3 Protease and Interference with Host C-Type Lectin Receptor-Mediated Entry

Abstract

Objective: This study aimed to perform a computational analysis of apigenin and luteolin, focusing on their biological activities, pharmacokinetic properties, and interactions with dengue virus serotype 2 (DENV-2) proteins and host cell receptors associated with viral entry.Material and Methods: The biological activities of the compounds were first predicted using PASS Online to evaluate their potential pharmacological profiles. Pharmacokinetic properties, including gastrointestinal absorption, skin permeation, blood–brain barrier penetration, cytochrome P450 interactions, bioavailability score, and overall drug-likeness, were assessed using SwissADME. In addition, toxicity parameters, such as LD₅₀ values and organ-specific toxicities, were predicted using ProTox 3.0. Subsequently, molecular docking simulations were performed using the SeamDock web server to evaluate the binding affinities of the compounds with dengue viral proteins and host receptor targets.Results: Both compounds exhibited favorable pharmacokinetic characteristics and low predicted toxicity, alongside antioxidant and anti-inflammatory activities. Docking simulations revealed that luteolin had a slightly stronger affinity (−7.74 kcal/mol) than apigenin (−7.67 kcal/mol) toward the NS2B-NS3 protease, particularly at allosteric sites. In addition, both flavonoids displayed interactions with host C-type lectin receptors, suggesting potential interference with viral attachment and entry mechanisms.Conclusion: These computational findings highlight apigenin and luteolin as promising anti-dengue candidates with dual mechanisms of action through viral protease inhibition and host receptor interactions, supported by favorable pharmacokinetic and safety profiles.