title: Use of acetylcholine binding protein in the search for novel alpha7 nicotinic receptor ligands. In silico docking, pharmacological screening, and X-ray analysis.
abstract: 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 alpha7 nAChRs. Two high affinity ligands were cocrystallized with AChBP, revealing the binding mode in the orthosteric site. Functional studies revealed that these two ligands caused inhibition of the alpha7, alpha4beta2, and 5HT(3) receptors. The noncompetive blockade of the receptors suggests 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.
authors.affiliation: Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: Ulens
authors.forename: Atilla
authors.initials: A
authors.lastname: Akdemir
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.forename: Rene
authors.initials: R
authors.lastname: van Elk
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch