Acetylcholine nicotinic receptors: finding the putative binding site of allosteric modulators using the “blind docking” approach

Bogdan Iorga (1) , Denyse Herlem (1) , Elvina Barré (1) , Catherine Guillou (1)

1 ICSN - Institut de Chimie des Substances Naturelles

Allosteric potentiation of acetylcholine nicotinic receptors is considered as one of the most promising approaches for the treatment of the Alzheimer's disease. However, the exact localisation of the allosteric binding site and the potentiation mechanism at the molecular level are presently unknown. We performed the "blind docking" of three known allosteric modulators (galanthamine, codeine and eserine) with the Acetylcholine Binding Protein and models of human a7, a3b4 and a4b2 nicotinic receptors, created by homology modelling. Three putative binding sites were identified in the channel pore, each one showing different affinities for the ligands. One of these sites is localised opposite to the agonist binding site and is probably implicated in the potentiation process. On the basis of these results, a possible mechanism for the nicotinic acetylcholine receptors (nAChRs) activation is proposed. The present findings may represent an important advance for understanding the allosteric modulation mechanism of nAChRs.

Domaines: Chimie

Bogdan Iorga, Denyse Herlem, Elvina Barré, Catherine Guillou. Acetylcholine nicotinic receptors: finding the putative binding site of allosteric modulators using the “blind docking” approach. Journal of Molecular Modeling, 2006, 12 (3), pp.366-372. ⟨10.1007/s00894-005-0057-z⟩. ⟨hal-03161516⟩