Targeting SmTGR in Schistosomiasis: Identification and Characterization of NPC470090 as a Promising Lead Compound

Schistosomiasis affects over 250 million people and relies almost exclusively on praziquantel, which is ineffective against juvenile worms and faces emerging resistance. New therapeutic strategies are urgently needed. Schistosoma mansoni thioredoxin–glutathione reductase (SmTGR), a parasite-specific redox enzyme without a direct mammalian counterpart, was prioritized as a selective target. A curated natural-product library was screened by structure-based docking. Top hits were advanced to 150 ns molecular dynamics simulations and MM/PBSA free-energy calculations. Complex stability was assessed by RMSD, RMSF, hydrogen-bond persistence, and energy decomposition. Three candidates (NPC178134, NPC471688, NPC470090) exhibited favourable docking and pharmacokinetic profiles. Of these, NPC470090 emerged as the strongest lead, maintaining stable binding in the catalytic cavity with persistent hydrogen bonds, low ligand RMSD, and the most favourable binding free energy (−120.76 ± 14.31 kJ·mol⁻¹). By comparison, praziquantel displayed weaker binding (−99.07 ± 12.25 kJ·mol⁻¹) and limited stabilizing interactions. Protein-backbone RMSD and active-site RMSF supported stable complex formation without disruptive conformational changes. This study validates SmTGR as a tractable, parasite-specific drug target and identifies NPC470090 as a promising natural-product-derived chemotype. The findings provide a rational framework linking computational screening to translational development. Immediate priorities include enzymatic inhibition assays, cytotoxicity profiling, SAR-guided optimization, and in vivo testing.