Prediction of the neurotoxic mechanisms of the pesticide phorate using network toxicology, molecular docking, and molecular dynamics simulation

Phorate is an organophosphate pesticide that may cause neurotoxicity, although the exact mechanisms remain unclear.This study aimed to elucidate the mechanisms of neurotoxicity caused by phorate overexposure using network toxicology, molecular docking, and molecular dynamics simulation.We identified 104 potential targets and 20 core targets associated with phorate-induced neurotoxicity. Key targets, including MMP9, CASP1, and KEAP1, may be involved in neuroactive ligand-receptor interaction signalling, as well as the cAMP and calcium signalling pathways. Furthermore, molecular dynamics simulations were conducted on the KEAP1 and CASP1 protein-ligand complexes, which demonstrated the highest binding stabilities in molecular docking analysis. The binding free energies were calculated to be -27.08 and -22.80 kcal/mol for KEAP1 and CASP1, respectively, indicating that both complexes are thermodynamically stable.The methodology used in this study facilitates the identification and assessment of previously unexplored agrochemical toxicity pathways and molecular mechanisms. These findings suggest a novel approach to controlling pesticide residues and screening drugs.