Molecular Simulations On The α7Nicotinic Acetylcholine Receptors And The Partial Agonists

a7-nAChR is the drug target for Parkinson’s disease, myasthenia gravis and neuropathic pain. So far, the studies on its full agonists have been complete. In our study, we focused on the partial agonists of a7-nAChR, which can also active the receptors as the full agonists. In comparison with full agonists, partial agonists possess less toxic, produce fewer side effects and have less addiction liability. However, the high-resolution crystal structure of a7-nAChR is still unavailable, experiment on a7-nAChR and partial agonsits is difficult to carry out. So the molecular simulation on a7-nAChR and partial agonsits is necessary.In the current study, the model of a7-nAChR which was built by homology modeling before this article was used as the receptor, four partial agonists and one full agonist were chosen to be the ligands. The four partial agonists were4-OH-DMXBA, S24795, JN403and Tropisetron, respectively and the full agonist was ACh. In the study, AutoDock was used to do the molecular docking, and then Amber was applied to the molecular dynamics and MM/GBSA method was used to calculate the binding free energy of the systems.Some critical residues in the complexes of a7-nAChR with ligands were identified by analysing the trajectory files and comparing the structures of AChBP complexes and a7-nAChR complexes. The determinate of the critial residues was not only helpful to identify the binding model and the mechanism of action of a7-nAChR with partial agonists, but also useful to demonstrate the necessity of our research.Energy calculations using MM/GBSA suggested that the van der Waals term (AEvdw) was the main driving force for the binding of the partial agonists to a7-nAChR. Finally, the efficacy of the ligands was determined to be related to the opening of the C-loop, the volume of the ligands, the binding affinity and some other unknown factors.