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://ucris.univie.ac.at/portal/en/publications/a-binding-mode-hypothesis-of-tiagabine-confirms-liothyronine-effect-on-aminobutyric-acid-transporter-1-gat1(13a95dd3-534f-43d3-98cd-e41bb95be19a).html