Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Nat Chem Biol. 2012 Mar 25;8(5):455-64. doi: 10.1038/nchembio.917.

Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands.

Author information

  • 1Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.

Abstract

Benzodiazepines exert their anxiolytic, anticonvulsant, muscle-relaxant and sedative-hypnotic properties by allosterically enhancing the action of GABA at GABA(A) receptors via their benzodiazepine-binding site. Although these drugs have been used clinically since 1960, the molecular basis of this interaction is still not known. By using multiple homology models and an unbiased docking protocol, we identified a binding hypothesis for the diazepam-bound structure of the benzodiazepine site, which was confirmed by experimental evidence. Moreover, two independent virtual screening approaches based on this structure identified known benzodiazepine-site ligands from different structural classes and predicted potential new ligands for this site. Receptor-binding assays and electrophysiological studies on recombinant receptors confirmed these predictions and thus identified new chemotypes for the benzodiazepine-binding site. Our results support the validity of the diazepam-bound structure of the benzodiazepine-binding pocket, demonstrate its suitability for drug discovery and pave the way for structure-based drug design.

PMID:
22446838
[PubMed - indexed for MEDLINE]
PMCID:
PMC3368153
Free PMC Article

Publication Types, MeSH Terms, Substances, Secondary Source ID, Grant Support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Write to the Help Desk