title: The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABAA receptor.
abstract: A Catalyst pharmacophore model has been developed for the benzodiazepine site within the GABA(A) receptor complex. The model is based on a pharmacophore model originally proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) and further developed by Kahnberg et al. (J. Med. Chem. 2002, 45, 4188-4201). The Catalyst pharmacophore model has been validated by using a series of flavonoids with varying affinities for the benzodiazepine receptor and has then been used as a search query in database searching with the aim of finding novel structures which have the possibility to be modified into novel lead compounds. Five of the hits from the database searching were purchased and their affinities for the benzodiazepine site of the GABA(A) receptor were determined. Two of the compounds displayed K(i) values below 10 microM. The substance showing highest potency in-vitro displayed an affinity of 121 nM making it an interesting compound for optimization. The false positive compounds (K(i) values >10 microM affinities) have been analysed in terms of conformational energy penalties and possibilities for hydrogen bond interactions. The analysis clearly demonstrates the need for post processing of Catalyst hits.
authors.affiliation: Department of Organic and Bioorganic Chemistry, Lund University, P.O.Box 124, S-22100 Lund, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Kahnberg
authors.forename: Michael H
authors.initials: MH
authors.lastname: Howard
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Mogens
authors.initials: M
authors.lastname: Nielsen
authors.forename: Elsebet Østergaard
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Olov
authors.initials: O
authors.lastname: Sterner
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pettersson
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry*; D018757:GABA Modulators / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism
chemical_list: D005419:Flavonoids; D018757:GABA Modulators; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines