Enantioselective interaction with acetylcholinesterase of an organophosphate insecticide fenamiphos

Enantioselectivity in the environmental behavior and ecotoxicity of chiral pesticide is widely observed. However, the investigation of the enantioselective mechanisms remains limited. In this study, we used fenamiphos (FAP), an organophosphorus insecticide, to study enantioselectivity in toxicity to arthropods and the inhibition potential towards acetylcholinesterase (AChE) in the rat pheochromocytoma 12 (PC 12) cell line. Furthermore, we carried out molecular docking to help explain the mechanisms of enantioselective toxicity of FAP. The two enantiomers of FAP were successfully separated and identified as R‐(+)‐FAP and S‐(?)‐FAP. Toxicological assays revealed that R‐(+)‐FAP was 2.4‐fold more toxic than S‐(?)‐FAP to Daphnia magna and approximately threefold more to PC12 cells. Based on molecular docking results, dynamic simulation shows that strong hydrophobic interactions and a key hydrogen bond can only exist between R‐(+)‐FAP and AChE, which helps explain the preference of R‐(+) binding to AChE over that of the S‐(?)‐enantiomer, and supports our biological results. Our present study considers the impact of stereochemistry on ecotoxicological effects and, ultimately, on development of environmentally safe, insecticidally efficient pesticides. Chirality 2010. © 2009 Wiley‐Liss, Inc.