Abstract
Paraquat (PQ) is a highly toxic herbicide that is lethal and causes fatal multi-organ toxicity in humans, as there are no effective treatments available. Despite extensive studies on new therapeutic targets and lead compounds, the existing approaches for treating PQ-induced toxicity remain inadequate and challenging, highlighting the urgent need for curative therapeutic approaches of great significance. This study uses the computational approach to identify the potential phytoconstituent-based antioxidant exhibiting the potential binding affinity with the Toll-interacting protein (TOLLIP). Initially, using molecular docking, mechanics-generalized born surface area (MM/GBSA) binding energy calculation, and ADME-Tox (Absorption, Distribution, Metabolism, Excretion, and Toxicity), a total of 89 phytoconstituents were evaluated for binding affinity to the TOLLIP. The five compounds Arbutin, Coumaric acid, Ethyl gallate, Ferulic acid, and Vanillic acid with significant binding affinity and pharmacokinetic properties, were further subjected to molecular dynamic simulation, trajectory analysis (RMSD, RMSF, Radius of gyration), binding free energy, PCA, DCCM. Our extensive computational analysis identified the Ethyl gallate-TOLLIP complex as a promising candidate, characterized by exceptional structural stability, minimal fluctuation, and the highest negative binding free energy. Therefore, Ethyl gallate may act as a potent therapeutic agent for mitigating paraquat-induced toxicity by targeting TOLLIP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00455-w.