Ligand selectivity for the acetylcholine binding site of the rat α4β2 and α3β4 nicotinic subtypes investigated by molecular docking

The homology models of the extracellular domains of the neuronal alpha 4 beta 2 (pdb code: 1ole) and ganglionic alpha 3 beta 4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1 - 15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha 4 subunit and establishing a characteristic H-bond with the Lys 77 on the H side of the beta 2 subunit. The nontoxic ligands such as 33bMet (3), (S)-A-85380 (4), and acetylcholine (6) docked into cluster 2 with the same.,pi-cation interaction but with the rest of the molecule occupying a different moiety of the binding pocket. Molecular docking into the alpha 3 beta 4 subtype showed that both enantiomers of 1 (1a and 1b) are representative templates for ligands with affinity toward this ganglionic nAChR subtype. The ranking scores of the docked molecules confirm the existence of structure-dependent subtype selectivity and shed light on the design of specific and selective alpha 4 beta 2 nAChR subtype ligands.