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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Pia Kahnberg
  • MH Howard
  • T Liljefors
  • M Nielsen
  • EO Nielsen
  • Olov Sterner
  • I Pettersson
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Organic Chemistry
Original languageEnglish
Pages (from-to)253-261
JournalJournal of Molecular Graphics & Modelling
Volume23
Issue number3
Publication statusPublished - 2004
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)