He_2025_ACS.Omega_10_48684

Chiral organophosphorus pollutants are widely distributed in different environmental matrices, but their health risks to humans remain insufficiently explored. This study explored the acetylcholinesterase (AChE)-mediated enantioselective neurotoxicity of dioxabenzofos on SH-SY5Y cells and elucidated the microscopic mechanisms underlying neurotoxicity at the enantiomeric level. Cellular assays exhibited that dioxabenzofos displayed significant enantioselectivity in inhibiting the intracellular AChE activity, with IC(50) values of 17.2 microM and 5.28 microM, respectively, reflecting differences in bioaffinity between both enantiomers and intracellular AChE. Modes of neurotoxic action suggest that the different orientations of enantiomers enable them to form conjugated interactions and substantial hydrogen bonds with key residues, while inherent conformational dynamics and flexibility enhance the bioaffinity of (S)-dioxabenzofos toward AChE. Energy decomposition results indicated that the binding free energy (-15.43 kcal mol(-1)) of (R)-dioxabenzofos to AChE was larger than that of (S)-dioxabenzofos (-23.55 kcal mol(-1)), and key residues such as Trp-86, Tyr-124, Ser-203, Tyr-337, and His-447 at the active site were found to contribute differently to the enantioselective neurotoxic effects. Clearly, these findings provide mechanistic insights into assessing the neurotoxicity risks associated with human exposure to chiral dioxabenzofos.