Integrating Molecular Docking, Dynamics, and AI-Based ADMET Prediction to Decipher the Toxicity Profile of...

Isometamidium chloride (ISM) is a widely used trypanocidal drug for treating animal trypanosomiasis, despite concerns about toxicity, and emerging drug resistance. A comprehensive in silico evaluation integrating molecular interaction analysis, pharmacokinetic profiling, toxicity prediction, and molecular dynamics simulations has not yet been reported. Owing to the unavailability of a crystal structure for Trypanosoma evansi, the co-crystal structure of the catalytic domain of thymidine kinase from T. brucei (5FUW, 2.20 Å) was used for computational studies. ISM exhibited strong binding affinity and stable protein-ligand interactions throughout a 100 ns MD simulation. ADMET analysis predicted high gastrointestinal absorption, potential CYP-mediated interactions, and toxicity risks. Compared with QS, ISM showed better drug likeness, complete compliance with Lipinski's rule, and a higher predicted bioavailability score. Collectively, these findings demonstrate that although ISM possesses favorable target affinity, its pharmacokinetic and safety limitations warrant structural optimization and safer formulation strategies for improved trypanocidal therapy.