A Binding Mode Hypothesis of Tiagabine Confirms Liothyronine Effect on γ-Aminobutyric Acid Transporter 1 (GAT1)
- Author(s)
- Andreas Jurik, Barbara Zdrazil, Marion Holy, Thomas Stockner, Harald H. Sitte, Gerhard Ecker
- Abstract
Elevating GABA levels in the synaptic cleft by inhibiting its reuptake carrier GAT1 is an established approach for the treatment of CNS disorders like epilepsy. With the increasing availability of crystal structures of transmembrane transporters, structure-based approaches to elucidate the molecular basis of ligand-transporter interaction also become feasible. Experimental data guided docking of derivatives of the GAT1 inhibitor tiagabine into a protein homology model of GAT1 allowed derivation of a common binding mode for this class of inhibitors that is able to account for the distinct structure-activity relationship pattern of the data set. Translating essential binding features into a pharmacophore model followed by in silico screening of the DrugBank identified liothyronine as a drug potentially exerting a similar effect on GAT1. Experimental testing further confirmed the GAT1 inhibiting properties of this thyroid hormone.
- Organisation(s)
- External organisation(s)
- Medizinische Universität Wien, Austrian Research Centers GmbH (ARC Seibersdorf)
- Journal
- Journal of Medicinal Chemistry
- Volume
- 58
- Pages
- 2149-2158
- No. of pages
- 10
- ISSN
- 0022-2623
- DOI
- https://doi.org/10.1021/jm5015428
- Publication date
- 03-2015
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301207 Pharmaceutical chemistry
- Keywords
- ASJC Scopus subject areas
- Drug Discovery, Molecular Medicine
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/13a95dd3-534f-43d3-98cd-e41bb95be19a