title: Acetylcholine binding protein (AChBP) as template for hierarchical in silico screening procedures to identify structurally novel ligands for the nicotinic receptors.
abstract: Hierarchical in silico screening protocols against the agonist bound acetylcholine binding protein (AChBP) crystal structure were efficient in identifying novel chemotypes for AChBP and the human α7 receptor. Two hit structures were cocrystallized with AChBP revealing intermolecular cation-π interactions with loop C but lacking intermolecular hydrogen bonding. The compounds act as competitive α7 receptor antagonists and as non-competitive α4β2 receptor inhibitors. These results underline the usability of AChBP in structure-based in silico screening strategies in finding novel scaffolds for the α7 receptor, but also illustrates some limitations of using AChBP as bait to find competitive α4β2 receptor ligands and α7 receptor agonists.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, The Netherlands.
authors.forename: Atilla
authors.initials: A
authors.lastname: Akdemir
authors.forename: Prakash
authors.initials: P
authors.lastname: Rucktooa
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.forename: Rene van
authors.initials: Rv
authors.lastname: Elk
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2