title: Identification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain.
abstract: A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK(i) ≥5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were identified. Binding studies with [(3)H]epibatidine on chimeric α7/5-HT(3) receptors yielded submicromolar inhibition constants for identified hits. Compared to a previous screening procedure that utilized the wild type Ls-AChBP crystal structure, the current study shows that the recently obtained α7/Ls-AChBP chimeric protein crystal structure is a better template for the identification of novel α7 receptor ligands.
authors.affiliation: Division of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey.
authors.forename: Atilla
authors.initials: A
authors.lastname: Akdemir
authors.forename: Ewald
authors.initials: E
authors.lastname: Edink
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D008024:Ligands; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D054852:Small Molecule Libraries; D064569:alpha7 Nicotinic Acetylcholine Receptor