Docking of lobeline, a partial agonist of nicotinic acetylcholine receptors (nAChRs), was investigated at once into crystallographic structures of acetylcholine binding proteins (AChBP) and into α7 and α4β2 nAChRs homology models, and compared to behavior of full agonists, nicotine and epibatidine. The homology models were built using as templates the different pocket geometries established in crystallographic AChBP structures. Systematic cross-docking of each ligand into binding pockets of the two other ligands as well as its self-docking into its own pocket were performed in order to better understand the structural features determining the binding of these three ligands chosen for their molecular diversity. In AChBPs, epibatidine and nicotine display similar docking scores in their own pocket and in other ligands pockets: in particular, they also dock favorably into the lobeline pocket. In opposite, lobeline displays different features: it only binds favorably to its own pocket in AChBPs. Furthermore, the docking poses observed starting from lobeline stereoisomers support the importance of the intramolecular hydrogen bond between the alcohol function of the β-phenyl- β-hydroxyethyl arm and the piperidinium proton for the lobeline binding to AChBP. For homology models, crossdockings are still discriminating and the specificity of lobeline for its binding pocket is conserved.
Keywords: AChBP, Lobeline, Docking, Diastereomer, cross-docking, agonists, nicotine, epibatidine, β-phenyl-β-hydroxyethyl arm, Ligand-Gated Ion Channels (LGICs), trans-membrane channel proteins, central nervous system (CNS)
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