Enantioselective interaction with acetylcholinesterase of an organophosphate insecticide fenamiphos

Abstract

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.

Enantioselective Cytotoxicity Profile of o,p’-DDT in PC 12 Cells

“…Using a computer-aided molecular docking simulation tool widely applied in drug designs, we determined that the three-dimensional (3-D) chemical structure of R -fenamiphos favors its hydrogen bonding with the active site of the acetylcholinesterase. Unfortunately, this simulation approach cannot be readily applied to distinguish the enantioselectivities of o,p ’-DDT because the evaluation must consider the 3-D structure of the chiral pesticide, but also the chiral environment of the unknown biological receptor [37].…”

Cytotoxicity and DNA damage of five organophosphorus pesticides mediated by oxidative stress in PC12 cells and protection by vitamin E

“…Inhibition of AchE by OPs causes accumulation of acetylcholine at cholinergic synapses; over-stimulation of muscarinic and nicotinic receptors, and an ensuing "cholinergic syndrome". [1,2] In addition, OPs elicit their toxicities via other pathways including cytotoxicity, [3][4][5] genotoxicity, [6][7][8] disruption of sex hormones and reproduction. [9,10] These toxic effects of OPs have attracted much interest in the search for the involved mechanisms.…”

Understanding the endocrine disruption of chiral pesticides: The enantioselectivity in estrogenic activity of synthetic pyrethroids

“…The definition of the active site of ER is from a file containing a list of residues within a 5 Å radius of the ligand. Other parameters were set as previously described [27].…”