title: Exploring α7-Nicotinic Receptor Ligand Diversity by Scaffold Enumeration from the Chemical Universe Database GDB.
abstract: Virtual analogues (1167860 compounds) of the nicotinic α7-receptor (α7 nAChR) ligands PNU-282,987 and SSR180711 were generated from the chemical universe database GDB-11 by extracting all aliphatic diamine analogues of the aminoquinuclidine and 1,4-diazabicyclo[3.2.2]nonane scaffolds of these ligands and converting them to the corresponding aryl amides using five different aromatic acyl groups. The library was ranked by docking to the nicotinic binding site of the acetylcholine binding protein (AChBP, 1UW6.pdb) using Autodock and Glide. Thirty-eight ligands derived from the best docking hits were synthesized and tested for modulation of the acetylcholine signal at the human α7 nAChR receptor expressed in Xenopus oocytes, leading to competitive and noncompetitive antagonists with IC50 = 5-7 μM. These experiments demonstrate the first example of using GDB in a fragment-based approach by diversifying the scaffold of known drugs.
authors.affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Noemi
authors.initials: N
authors.lastname: Garcia-Delgado
authors.affiliation: Department of Neuroscience, Medical Faculty, 1, rue Michel Servet CH-1211 Geneva 4, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Kong T
authors.initials: KT
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Ruud
authors.initials: R
authors.lastname: van Deursen
authors.affiliation: Department of Neuroscience, Medical Faculty, 1, rue Michel Servet CH-1211 Geneva 4, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
keywords: Virtual libraries; docking; electrophysiology; nicotinic receptor; virtual screening