Assessing the nicotinic acetylcholine receptor-mediated enantioselective neurotoxicity of a neonicotinoid-like pollutant, chiral sulfoxaflor: Insight from the two asymmetric centers

Abstract

Chiral sulfoxaflor is widely present in environmental matrices; however, the health hazards of this neonicotinoid-like pollutant remain poorly understood. This study investigated the nicotinic acetylcholine receptor (nAChR)-mediated neurotoxicity of sulfoxaflor at the enantiomeric level and elucidated the distinct roles of its two chiral centers. Results showed that the toxic response of nAChR to sulfoxaflor exhibits significant enantioselectivity and the affinity of α₇ nAChR with (R,S)-/(S,S)-sulfoxaflor (－35.34/－34.84 kcal mol⁻¹) is higher than those of their antipodes (－22.08/－22.76 kcal mol⁻¹). The conjugations of (R,S)-/(S,S)-sulfoxaflor in agonistic mode at the orthosteric site induces crucial residues (e.g., Trp-147, Tyr-186, Leu-117) to shift toward the binding position (RMSF: 0.0968 nm to 0.3959/0.3801 nm), which disturbs the intrinsic conformational flexibility of α₇ nAChR (random coil: 18.16–23.65 %/22.15 %), prompting (R,S)-/(S,S)-sulfoxaflor to exhibit enhanced activated efficacy. Furthermore, chirality at the sulfur atom plays a key role in the electrostatic contribution (ΔG_ele) to be different (－23.55/－22.3/－11.39/－12.73 kcal mol⁻¹), rendering sulfoxaflor a higher enantioselective neurotoxicant. This study could pave away for untangling the health hazards associated with sulfoxaflor and prompt the legislature to develop environmental regulations for pollutants containing multiple chiral centers.