Computational evidence for the ligand selectivity to the α4β2 and α3β4 nicotinic acetylcholine receptors

The homology models of the α4β2 and α3β4 nicotinic acetylcholine receptors (nAChRs) suggest that the two nAChR subtypes are different in their ligand-binding pockets due to the non-conserved residues in the β-subunits. The docking of nicotine, epibatidine, A-84543, and the two analogs of A-84543 ligands 1 and 2 to the homology models of α4β2 and α3β4 is presented. It is found that the protonated amino groups of these ligands bind to the α-subunits, whereas the remaining parts of the ligands bind to the β-subunits. The two non-conserved amino acids Lys77 and Phe117 in the β2-subunit corresponding to Ile77 and Gln117 in the β4-subunit are identified to be the key players determining the binding modes of the ligands. We demonstrate how the increase in the number of the atoms connecting the pyrrolidine and pyridine rings in A-84543, 1, and 2, and an introduction of the alkynyl substituent in the pyridine ring affect the binding and shift the selectivity of these ligands toward the β2-containing receptors. Further improvement in affinity and selectivity in this and other series of the ligands may be achieved by designing molecules that would specifically target the non-conserved regions in nAChRs.