Modeling subtype-selective agonists binding with α4β2 and α7 nicotinic acetylcholine receptors: Effects of local binding and long-range electrostatic interactions

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 results demonstrate that the subtype selectivity of the agonists binding with α4β2 and α7 nAChRs is affected by both local binding and long-range electrostatic interactions between the receptors and the protonated structures of the agonists. The effects of the long-range electrostatic interactions are mainly due to the distinct difference in the net charge of the ligand-binding domain between the two nAChR subtypes. For the α4β2-selective agonists examined, the microscopic binding modes with the α4β2 nAChR are very similar to the corresponding modes with the α7 nAChR, and therefore, the subtype selectivity of these agonists binding with α4β2 and α7 nAChRs is dominated by the long-range electrostatic interactions. For the α7-selective agonists, their microscopic binding modes with the α7 nAChR are remarkably different from those with the α4β2 nAChR so that the local binding (including the hydrogen bonding and cation-π interactions) with the α7 nAChR is much stronger than that with the α4β2 nAChR. The calculated phenomenological binding free energies are in good agreement with available experimental data for the relative binding free energies concerning the subtype selectivity of agonists binding with the two different nAChR subtypes. The fundamental insights obtained in the present study should be valuable for future rational design of potential therapeutic agents targeted to specific nAChR subtypes.