Molecular interaction studies of endosulfan with the cholinergic pathway targets – An insilico approach

Abstract

Endosulfan (ED) is a broad-spectrum organochlorine insecticide used around the world in agriculture to control insect pest. ED leaches to soil become persistent in environment. The main ED derivatives found in environmental sources is endosulfan sulfate, which leads both acute and chronic toxicity. The principal target of ED is nervous system. In the present study, the interaction of α-ED with cholinergic pathway proteins and receptors were accessed by insilico methods. Homology modeling of human adult and fetal muscle-type nicotinic acetylcholine receptor (nAChRs) was performed using SWISS-MODEL molecular modeling server with known crystal structure of Torpedo nAChR as a template. Both embryonic and adult nAChR that differ in a single subunit were modeled. Docking studies were carried out on α-ε and α-δ subunit interfaces of human adult nAChR and α-γ and α-δ subunit interfaces of human fetal nAChR with ED. The structure of acetylcholine (ACh), a natural ligand of the modeled receptor was used as a reference compound for docking studies. Docking of ACh and ED with the key enzymes in the pathway acetylcholine esterase (AChE) and docking of choline and ED with choline acetyltransferase (ChAT) were also performed using available molecular modeling software. The results showed that ED binding to all the selected targets, but in the case of modeled human nAChR, ED showed higher affinity towards the modeled fetal nAChR subunit interface than the modeled adult receptor. The ED showed higher binding affinity towards the ChAT. Our results implicated that more toxic effect of ED during the developmental stages.