Structural determinants of imidacloprid-based nicotinic acetylcholine receptor inhibitors identified using 3D-QSAR, docking and molecular dynamics

Nicotinic acetylcholine receptor (nAChR) is a target for insect-selective neonicotinoid insecticides (NNs), exemplified by imidacloprid (IMI). In the present study, 78 IMI derivatives reported as inhibitors of Drosophila melanogaster nAChR ( Dm- nAChR) and Musca domestica nAChR ( Md- nAChR) were used for three-dimensional quantitative structure–activity relationship (3D-QSAR) studies. Two optimal models with good predictive power were obtained: Q 2 = 0.64, R 2 pred = 0.72 for Dm- nAChR, and Q 2 = 0.63, R 2 pred = 0.62 for Md- nAChR. In addition, homology modeling, molecular dynamic (MD) simulation, and molecular docking also showed that amino acids located within loops A, C, D and E play key roles in the interaction of Dm -/ Md -nAChR with NNs. This is highly consistent with the results of graphical analysis of 3D-QSAR contour plots. Mutation analysis also implicates the Y/S mutation within loop B as being associated closely with NN resistance in Drosophila and Musca . The results obtained lead to a better understanding not only of interactions between these antagonists and Dm -/ Md -nAChR, but also of the essential features that should be considered when designing novel inhibitors with desired activities. Figure Left panel Structure of imidacloprid (IMI)—an insect-selective neonicotinoid insecticide (NN). Right panel IMI interaction with Drosophila / Musca nicotinic acetylcholine receptor (nAChR)