Acetylcholine nicotinic receptors: finding the putative binding site of allosteric modulators using the "blind docking" approach
Allosteric potentiation of acetylcholine nicotinic receptors is considered to be one of the most promising approaches for the treatment of Alzheimer's disease. However, the exact localization of the allosteric binding site and the potentiation mechanism at the molecular level are presently unknown. We have performed the "blind docking" of three known allosteric modulators (galanthamine, codeine and eserine) with the Acetylcholine Binding Protein and models of human alpha 7, alpha 3 beta 4 and alpha 4 beta 2 nicotinic receptors, created by homology modeling. Three putative binding sites were identified in the channel pore, each one showing different affinities for the ligands. One of these sites is localized opposite to the agonist binding site and is probably implicated in the potentiation process. On the basis of these results, a possible mechanism for nicotinic acetylcholine receptor (nAChRs) activation is proposed. The present findings may represent an important advance for understanding the allosteric modulation mechanism of nAChRs.
acetylcholine nicotinic receptors allosteric modulators docking