Neonicotinoid Compounds And The Interaction Of The Nicotinic Acetylcholine Receptor And Selective Study

This dissertation consisted of three chapters. Chapter one was the review of the structure and function of nAChRs, the type of the subunit and subtype, and the interaction mechanism with neonicotinoids. Several general methods of computer aided drug design were also concluded.Chapter two was the study of the interaction mechanism between the target and some typic neonicotinoids through homology modeling, molecular docking and the point mutant methods. The binding results of AChBP and IPPA156011 were evaluated with the molecular docking. The study suggested that water was not very important to the interaction mechanism of IPPA156011A binding with AChBP. The binding ability between imidacloprid and Myzus persicae or Pardosa pseudoanulata was compared by sequence alignment, homology modeling and molecular docking as well. The dimers of N1α1/Rp Mpβ1 and N1α1/Rp Mpβ1-3M which N1α1/Rp Mpβ1 contains R81Q,N137G,F190W three mutants were modeled by homology modeling. Then molecular docking were used to calculate the binding ability of imidacloprid and the models. Nlal/RβMpβ1 showed the direct interaction between R81 and imidacloprid, but in the model of N1α1/Rβmpβ1-3M, Q81 located apart from imidacloprid. The hydrogen bond between R81 and the nitro group of imidacloprid determined the selectivity of imidacloprid between target insects and other species.Chapter three was the study of the selectivity of imidacloprid with Drosophila melanogasterα7 and hunmanα4β2 nAChRs by homology modeling and molecular dynamics. After modeled the two nAChR with imidacloprid and waters which were in the binding site by homology modeling,20ns molecular dynamics were taken by AMBER10 to compare the selectivity of imidacloprid between different species. The RMSD during 20ns of imidacloprid in two models showed that imidacloprid in Dα7 model was more stable than in hunmanα4β2 model. Waters in the binding site were very important in the binding between imidaclopird and Dα7 model through the calculation of hydrogen bond interaction. The waters could not only conform hydrogen bond with the residues around the binding site, but also with the nitro of imidacloprid pyridine cycle. The binding energy was also calculated by AUTODOCK4.1. The energy results suggested that imidacloprid could hold the active construction with lower binding energy in Dα7 model. Imidacloprid in hunmanα4β2 model could not keep the active construction suggested that the interaction between imidacloprid and Dα7 model were stronger than imidacloprid and hunmanα4β2 model. The interaction mechanism between imidacloprid and Dα7 model contains hydrogen bond,π-πinteraction, water bridge, C-H…πinteraction and so on.