Rationally Designed Functionalized Phytochemical‐Conjugated Fullerene Quantum Dots Inhibiting Viral Chaperone Activity and RNA‐Dependent RNA Polymerase in Nipah Virus

Nipah virus (NiV) causes a staggering 40%–70% mortality in humans. Studies focusing on inhibiting NiV entry or replication have yielded modest results. The purpose of this study was to identify safe and effective drugs for treating NiV disease by screening multipotent repurposable drugs/ligands through target‐based drug screening and then translating the top‐performing ligands into multifunctional antiviral nanomedicines using rational molecular engineering. We envisioned that targeting multiple molecular machineries crucial for NiV RNA synthesis, recruitment, and packaging by simultaneously inhibiting viral chaperone activity and RNA‐dependent RNA polymerase (RdRp) can usurp NiV activation, replication, and propagation together. By amalgamating virtual screening, molecular docking, molecular dynamics (MD), quantitative structure–activity relationship, and ADMET approaches, we found that andrographolide and stigmasterol hold strong potential to selectively inhibit NiV phosphoprotein (P; binding energy, B.E.: −6.0 kcal/mol) and nucleoprotein (N; −9.2), respectively, at specific P‐N interacting sites crucial for chaperone activity and recruitment of viral RNA. Interestingly, upon covalently conjugating functionalized andrographolide and stigmasterol (PO 4 /COOH) with C20 fullerene quantum dots (~0.4 nm), their binding affinities toward P (−6.47) and N proteins (−13.5) increased further, together with strong inhibitory potential against NiV RdRp (−10.5 and −9.55, respectively). MD simulations revealed strong binding affinities with stable hydrogen bonding, structural integrity, and overall compactness in ligand‐target complexes, justifying the docking results. Drug‐likeness and ADMET studies indicated appreciable oral absorption and toxicity for the ligands and nanoparticles. Our pioneering work thus warrants further investigations for utilizing andrographolide, stigmasterol, and their functionalized fullerene nanoconjugates for synergistically combating NiV infections.