Molecular Modeling Of Nicotinic Acetylcholine Receptor

The nicotinic acetylcholine receptor (nAChR) is ligand-gated ion channel complex for rapid excitatory neurotransmission. It is widely distributed in the insect central nervous system and constitutes a major target for insecticide action. The functional architecture and diversity of insect nAChRs are superficially understood in contrast to their vertebrate counterparts. To explore the mechanism of selective binding of neonicotinioids and design higher potent and selective incesticdes, in this study, three-dimensional structures of fruil fly (Drosophila melanogaster), peach-potato aphid (Myzus persicae), brown planthopper (Nilaparvata lugens) and rat (Rattus norvegicus) nAChR were constructed by homology modeling. Fifteen designed and synthetic neonicotinoid compounds with diversity of structure were docked into these obtained models, and the selective and resistent mechanisms of imidacloprid (IMI) were discussed.1. Three-dimensional models of fruit fly (α1)₂(β2)₃ and peach-potato aphid (α2)₂(β1)₃ nAChRs were generated by homology modeling, using the crystal structure of the acetylcholine-binding protein (AChBP) of Lymnaea stagnalis as a template, respectively; mammal rat (α4)₂(β2)₃ nAChR was generated by homology modeling using the nAChRα1 subunit of mus musculus as a template. Both of dynamics simulation and conformational analyses indicated that these consturcted models were reasonable and stable.2. Six commercial neonicotinoids were docked into fruit fly (α1)₂(β2)₃ and peach-potato aphid (α2)₂(β1)₃ nAChRs. The correlation between the binding free energies and activities was good, which indicate that the docking models were reliabile. Subsequently, fifteen designed compounds were docked into the two models and the calculated docking energies were in agreement with the experimental data. As the result, the fourth generation of neonicotinoid insecticide Cycloprid with large industrial prospect was found. 3. Neonicotinoid insecticide IMI was docked into the putative binding site of the fruit fly (α1)₂(β2)₃ and rat (α4)₂(β2)₃ nAChRs by Surflex-docking. Docking studies demonstrated that the fruit fly nAChR has greater specificity for IMI than the rat target-site and revealed that a lysine (or alternatively arginine or histidine) cationic residue in loop D of insect nAChR plays a key role in the selective interactions of heteromeric nAChRs with IMI.4. Homology models of the ligand binding domain of the wild-type and Y151S mutant brown planthopperα1 and ratβ2 nAChR subunits were generated based on the crystal structure of acetylcholine binding protein of Lymnaea stagnalis. IMI was docked into the putative binding site of wild-type and mutantα1β2 dimeric receptors by Surflex-docking, and the calculated docking energies were in agreement with experimental results. Docking studies suggested that the mutagenesis may cause the conformational changes of the wholeαsubunit to reduce the sensitivity of the binding site for IMI although the directed interactions between IMI and Tyr151 or Ser151 were not found.