| Abstract
| - The subtype-selective binding of 14 representative agonists with α4β2 and α7 nicotinic acetylcholine receptors(nAChRs) has been studied by performing homology modeling, molecular docking, geometry optimizations,and microscopic and phenomenological binding free energy calculations. All of the computational resultsdemonstrate that the subtype selectivity of the agonists binding with α4β2 and α7 nAChRs is affected byboth local binding and long-range electrostatic interactions between the receptors and the protonated structuresof the agonists. The effects of the long-range electrostatic interactions are mainly due to the distinct differencein the net charge of the ligand-binding domain between the two nAChR subtypes. For the α4β2-selectiveagonists examined, the microscopic binding modes with the α4β2 nAChR are very similar to the correspondingmodes with the α7 nAChR, and therefore, the subtype selectivity of these agonists binding with α4β2 andα7 nAChRs is dominated by the long-range electrostatic interactions. For the α7-selective agonists, theirmicroscopic binding modes with the α7 nAChR are remarkably different from those with the α4β2 nAChRso that the local binding (including the hydrogen bonding and cation−π interactions) with the α7 nAChRis much stronger than that with the α4β2 nAChR. The calculated phenomenological binding free energiesare in good agreement with available experimental data for the relative binding free energies concerning thesubtype selectivity of agonists binding with the two different nAChR subtypes. The fundamental insightsobtained in the present study should be valuable for future rational design of potential therapeutic agentstargeted to specific nAChR subtypes.
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