Structural and energetic basis of marine phytochemicals as dengue NS1 protein inhibitors

Dengue, spread by Aedes aegypti and Aedes albopictus, causes 390 million infections, 50 million illnesses, and 24,000 fatalities, including over 4.5 million in 2023. This work finds DENV NS1 protein anti-virals beyond CYD-TDV using in silico approaches. Virtual screening and molecular docking were used to evaluate binding affinities, followed by toxicity profiling to assess pharmacokinetics and safety. Molecular dynamics simulations (200 ns) and MM-GBSA calculations measured the stability and binding strength of the protein-ligand complexes. Additionally, HOMO-LUMO analysis was performed to predict electronic properties and chemical reactivity. Based on natural availability and clinical relevance, 1,191 seaweed metabolite compounds were evaluated for therapeutic application. Due to their strong binding affinities (-5.567, -4.776, and - 4.550 kcal/mol), excellent ADME profiles, and low toxicity, CIDs 359, 8768, and 11,500,585 were screened out. Molecular docking showed hydrophobic interactions with ILE93 and ILE218, suggesting a pocket-wide active site for each ligand. After docking, MM-GBSA demonstrated negative binding free energies, HOMO-LUMO gaps, RMSD, RMSF, Rg, SASA, and hydrogen bonds were measured in MD simulations to confirm the protein-ligand complex's stability. CID 11,500,585 excelled in cumulative protein RMSD, RMSF, and SASA. After the simulation, MM-GBSA analysis confirmed their stability, with CID 11,500,585 (3,4-dibromo-5-(2-hydroxyethyl) benzene-1,2-diol) from Rhodomela confervoides seaweed having the lowest value of -25.18 kcal/mol at 200 ns. It may suppress DENV proliferation. QSAR study suggested that this chemical is anti-viral, although in vivo and in vitro testing is needed.