title: Structural determinants of imidacloprid-based nicotinic acetylcholine receptor inhibitors identified using 3D-QSAR, docking and molecular dynamics.
abstract: 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.
authors: College of Veterinary Medicine, Northwest A & F University, Yangling, Shaanxi, China.
authors: Qinfan
authors: Q
authors: Li
authors: Xiangya
authors: X
authors: Kong
authors: Zhengtao
authors: Z
authors: Xiao
authors: Lihui
authors: L
authors: Zhang
authors: Fangfang
authors: F
authors: Wang
authors: Hong
authors: H
authors: Zhang
authors: Yan
authors: Y
authors: Li
authors: Yonghua
authors: Y
authors: Wang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry*; D019476:Insect Proteins / Q000737:chemistry* / Q000235:genetics; D007306:Insecticides / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D000073943:Neonicotinoids; D018733:Nicotinic Antagonists / Q000737:chemistry*; D009574:Nitro Compounds / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics; D040681:Structural Homology, Protein
chemical_list: D007093:Imidazoles; D019476:Insect Proteins; D007306:Insecticides; D000073943:Neonicotinoids; D018733:Nicotinic Antagonists; D009574:Nitro Compounds; D011978:Receptors, Nicotinic; C082359:imidacloprid