In Silico Identification of Potential Natural Inhibitors of Dengue Virus-2 (DENV-2) NS2B–NS3 Protease

Abstract

Background: Artificial Intelligence-driven drug discovery has recently made significant advances. Still, no Food and Drug Administration (FDA) approved antiviral drug is available for dengue treatment. The dengue virus NS2B–NS3 protease plays a critical role in viral replication and represents a promising therapeutic target. Aim: This study employed an integrated computational approach to identify potential phytochemical inhibitors of the NS2B–NS3 protease. Methods: Protein–protein interaction analysis was conducted to determine the most suitable protease conformation, and the 2FOM structure was selected based on its structural stability and active inhibitor-bound conformation. Initially, a library of over 5000 bioactive natural compounds was screened for anti-viral activity, from which 100 were shortlisted for molecular docking. Results: Docking analysis identified 27 compounds with high binding scores and favourable interactions with key catalytic residues. Subsequent drug-likeness and ADMET evaluation refined the candidates to nine potential compounds with acceptable pharmacokinetic and toxicity profiles. All these compounds demonstrated superior docking scores compared to the reference antiviral drugs. Conclusion: Curcumin, Quercetin, Gingerol, Flacourtoside A and Anacolosine emerged as the most potential lead molecules against Dengue virus infection. These findings support the potential of natural compounds as antiviral therapeutic molecules and need further molecular dynamics simulations and preclinical validation. Major Findings: From a library of over 5000 natural antiviral compounds, nine potential inhibitors of DENV-2 NS2B-NS3 protease were identified with favourable ADMET properties and superior docking scores compared to reference antiviral drugs. Curcumin, Quercetin, Gingerol, Flacourtoside A and Anacolosine emerged as the most promising lead molecules.