Elucidating the potential neurotoxicity of chiral phenthoate: Molecular insight from experimental and computational studies

Chiral organophosphorus pollutants are existed ubiquitously in the ecological environment, but the enantioselective toxicities of these nerve agents to humans and their molecular bases have not been fully elucidated. Using experimental and computational approaches, this story was to explore the neurotoxic response process of the target acetylcholinesterase (AChE) to chiral phenthoate and further decipher the microscopic mechanism of such toxicological effect at the enantiomeric level. The results showed that the toxic reaction of AChE with chiral phenthoate exhibited significant enantioselectivity, and (R)-phenthoate (K= 1.486 x 10(5) M-1) has a bioaffinity for the nerve enzyme nearly three times that of (S)-phenthoate (K= 4.503 x 10(4) M-1). Dynamic research outcomes interpreted the wet experiments, and the inherent conformational flexibility of the target enzyme has a great influence on the enantioselective neurotoxicological action processes, especially reflected in the conformational changes of the three key loop regions (i.e. residues His-447, Gly-448, and Tyr-449; residues Gly-122, Phe-123, and Tyr-124; and residues Thr-75, Leu-76, and Tyr-77) around the reaction patch. This was supported by the quantitative results of conformational studies derived from circular dichroism spectroscopy (alpha-helix: 34.7%30.2%/ 31.6%; beta-sheet: 23.6%19 -> 5%/20.7%; turn: 19.2%22 -> 4%/21.9%; and random coil: 22.5%27 -> 9%/25.8%). Meanwhile, via analyzing the modes of toxic action and free energies, we can find that (R)-phenthoate has a strong inhibitory effect on the enzymatic activity of AChE, as compared with (S)-phenthoate, and electrostatic energy (-23.79/ - 17.77 kJ mol(-1)) played a critical role in toxicological reactions. These points were the underlying causes of chiral phenthoate displaying different degrees of enantioselective neurotoxicity. (C) 2020 Elsevier Ltd. All rights reserved.