Computational Screening of Andrographis paniculata Constituents Against Dengue Virus NS2B–NS3 Protease: An Integrated In Silico Docking, ADMET, DFT and Molecular-Dynamics Study

Abstract

Background: Dengue is hyperendemic across South India, yet no licensed direct-acting antiviral exists. The dengue virus (DENV) NS2B–NS3 serine protease, which harbours the catalytic triad His51–Asp75–Ser135 and is essential for viral polyprotein maturation, is a validated antiviral target. Andrographis paniculata (kalmegh; nilavembu), a mainstay of South Indian and Ayurvedic antipyretic practice, is rich in diterpenoid lactones and flavonoids that are attractive scaffolds for computer-aided screening. Objective: To prioritise twelve A. paniculata constituents against the DENV NS2B–NS3 protease through an integrated in silico workflow combining molecular docking, ADMET/drug-likeness profiling, density-functional-theory (DFT) electronic descriptors and molecular dynamics (MD). Methods: Twelve curated constituents (six diterpenoids/lactones, four flavonoids, two phenolic acids) were energy-minimised and docked (five poses per ligand; sixty records) into the protease active site defined by the catalytic triad. Interaction profiles, ADMET/drug-likeness, DFT frontier-orbital descriptors and 100-ns MD with MM-GBSA binding free energy for the top three candidates were evaluated and combined into a ranking scheme.  Results: Best docking energies spanned −8.58 to −6.55 kcal/mol. Neoandrographolide ranked first (−8.58 kcal/mol; six H-bonds, nine hydrophobic contacts; favourable ADMET; zero Lipinski violations), followed by the flavonoids quercetin (−8.48) and luteolin (−8.24). Across all sixty poses ligands frequently contacted the catalytic triad (His51 24/60, Asp75 29/60, Ser135 27/60 poses). All twelve compounds had zero Lipinski violations; quercetin, luteolin, 7-O-methylwogonin and isoandrographolide carried ADMET "Review" flags (AMES-positive or predicted hepatotoxicity). DFT HOMO–LUMO gaps ranged 3.065–4.939 eV (andrographolide most reactive). All three MD complexes were stable (protein RMSD 1.80–2.11 Å); luteolin showed the most favorable MM-GBSA ΔG (−48.31 kcal/mol). Conclusion: The workflow prioritized neoandrographolide as the lead, with andrographolide also favorable and quercetin/luteolin as strong binders tempered by ADMET caveats.