Use of Acetylcholine Binding Protein in the Search for Novel α7 Nicotinic Receptor Ligands. In Silico Docking, Pharmacological Screening, and X-ray Analysis

Acetylcholine binding protein (AChBP) is widely considered as a functional and structural homologue of the ligand binding domain of Cys-loop receptors. We report the use of AChBP as template to identify ligands for the nicotinic receptors (nAChRs). An in silico screening protocol was set up and applied to crystal structures of AChBP. Several ligands containing a dibenzosuberyl moiety were identified and shown to bind with high affinity to AChBP and alpha 7 nAChRs. Two high affinity ligands were cocrystallized with AChBP, revealing the binding mode in the orthostetic site. Functional studies revealed that these two ligands Mests caused inhibition of the alpha 7, alpha 4 beta 2, and 5HT(3) receptors. The noncompetive blockade of the receptors suggest that these compounds act by steric hindrance of the channel. The analysis of the dual binding mode of these dibenzosuberyl-containing compounds can lead to better understanding of the complex mode of action of similar tricyclic ligands on Cys-loop receptors.