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.