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The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABA(A) receptor

Kahnberg, Pia LU ; Howard, MH; Liljefors, T; Nielsen, M; Nielsen, EO; Sterner, Olov LU and Pettersson, I (2004) In Journal of Molecular Graphics & Modelling 23(3). p.253-261
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... (More)
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 muM. 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 muM 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. (C) 2004 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Molecular Graphics & Modelling
volume
23
issue
3
pages
253 - 261
publisher
Elsevier
external identifiers
  • wos:000225333600005
  • pmid:15530821
  • scopus:7744242103
ISSN
1093-3263
DOI
10.1016/j.jmgm.2004.06.003
language
English
LU publication?
yes
id
7910e707-cd3d-46ac-9d7a-d90eeb8590b0 (old id 141122)
date added to LUP
2007-07-10 12:01:49
date last changed
2017-11-19 04:15:41
@article{7910e707-cd3d-46ac-9d7a-d90eeb8590b0,
  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 muM. 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 muM 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. (C) 2004 Elsevier Inc. All rights reserved.},
  author       = {Kahnberg, Pia and Howard, MH and Liljefors, T and Nielsen, M and Nielsen, EO and Sterner, Olov and Pettersson, I},
  issn         = {1093-3263},
  language     = {eng},
  number       = {3},
  pages        = {253--261},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Graphics & Modelling},
  title        = {The use of a pharmacophore model for identification of novel ligands for the benzodiazepine binding site of the GABA(A) receptor},
  url          = {http://dx.doi.org/10.1016/j.jmgm.2004.06.003},
  volume       = {23},
  year         = {2004},
}