Insecticide Molecular Designing Studies On The Ligands Acting On The Insect RyR And NAChR

Computational modeling methods play an important role in the discovery and optimization of pesticide leads. In this thesis, various computational modeling and molecular design methods were employed to evaluate the bioactive conformations of anthranilic diamide insecticides and perform virtual screening study against insect nicotinic acetylcholine receptor (nAChR).In chapter one, the important ion channel receptors of insecticide targets and the computational methods fulfilled in this thesis were reviewed, as well as the arrangement of the whole thesis was listed.In chapter two, combining DFT-based potential energy surface scanning with CoMFA and CoMSIA analyses, the bioactive conformations of anthranilic diamide insecticides targeting on insect ryanodine receptor (RyR) were disclosed from a series of low energy conformations. The 3D-QSAR models based on bioactive conformations showed the best statistically significance (CoMFA:r2=0.977,q2=0.740; CoMSIA:r2=0.952,q2=0.628) in all models. The findings on the bioactive conformations of anthranilic diamide insecticides might provide some clues for future insecticide design.In chapter three, the neonicotinoids-AChBP co-crystal structures were used to mimic insect nAChR, and two virtual screening strategies were applied to discover novel insecticidal compounds. Firstly, by a multiple targets screening strategy, six compounds were discovered with moderate activities against Aphis medicaginis Koch at 500 mg·L-1. Secondly, a strategy combining ligands similarity searching and docking was implemented. Considering the commercial neonicotinoids skeleton, imidacloprid (the most successful neonicotinoid) and flupyradifurone (the new developed neonicotinoid with low honeybee toxicity) were selected as queries for ligands similarity searching. By the followed docking study, dozens of compounds were revealed with novel structures.In chapter four, the whole thesis was briefly summarized.