Discovery of Novel Trypanothione Reductase Inhibitors through Pharmacophore Modeling, virtual Screening and Molecular Dynamics Simulations. New insights for Human African Trypanosomiasis

Human African Trypanosomiasis (HAT), caused by Trypanosome brucei , remains a critical health concern, with treatments such as Melarsoprol hampered by toxicity and resistance. To address this, we aimed to identify inhibitors targeting Trypanothione Reductase ( T.b TR), a key enzyme in the parasite’s survival. A pharmacophore model was derived from Melarsoprol and validated using Receiver Operating Characteristic (ROC) curves and Enrichment Factor (EF). Virtual screening of compound libraries identified two promising candidates, VS-1 and VS-2, based on superior docking scores. Subsequent molecular dynamics simulations confirmed the stability of the ligand-enzyme complexes, while binding free energy calculations revealed strong binding affinities for VS-1 and VS-2. Per-residue decomposition pointed critical interactions with active site residues, including MET 260, ASN 130, and HIS 128, contributing to the compounds’ stability and activity. These findings suggest that VS-1 and VS-2 are potential inhibitors of T.b TR, with better efficacy than Melarsoprol. However, further in vitro studies, including IC ₅₀ determination, cell cycle analysis, and morphological assays, are essential to confirm the therapeutic potential of these compounds for the treatment of HAT.