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. 2015 Mar 12;58(5):2149-58.
doi: 10.1021/jm5015428. Epub 2015 Feb 26.

A binding mode hypothesis of tiagabine confirms liothyronine effect on γ-aminobutyric acid transporter 1 (GAT1)

Andreas Jurik  1 , Barbara Zdrazil, Marion Holy, Thomas Stockner, Harald H Sitte, Gerhard F Ecker
Affiliations

A binding mode hypothesis of tiagabine confirms liothyronine effect on γ-aminobutyric acid transporter 1 (GAT1)

Andreas Jurik et al. J Med Chem. .

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.

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Figures

Figure 1
Figure 1
GABA, conformationally restricted analogs, and lipophilic aromatic derivatives.
Figure 2
Figure 2
Chemical structures and literature IC50 values of ligands with key modifications in linker length, polarity, and rigidity of the aromatic moiety.
Figure 3
Figure 3
Docking poses of tiagabine (turquoise) and analogs (orange) in 10 MD snapshots of the hGAT-1 model. Polar regions in blue, hydrophobic areas in yellow.
Figure 4
Figure 4
Dihedral energy landscape of 5-methyl-thiophen dihedral angles; configuration of the docking pose of 5 is marked in yellow. Constrained aromatic system of 7 is highlighted in red.
Figure 5
Figure 5
Pharmacophore model of tiagabine: hydrophobic (yellow), positive (blue), and negative (red) ionizable features in context with the GAT1 substrate binding site.
Figure 6
Figure 6
Compounds tested in the [3H]-GABA uptake assay: Enamine (red frame) and Drugbank hits (blue frame), and reference compounds (black frame).
Figure 7
Figure 7
Remaining uptake of [3H]-GABA in the presence of 100 μM of the respective compound (n = 3).
Figure 8
Figure 8
Inhibition curves of tiagabine (IC50 0.64 ± 0.07 μM, white squares) and liothyronine (IC50 13.0 ± 1.7 μM, black squares).
Figure 9
Figure 9
Pharmacophoric fit of 18 and 27a. Features are colored according to Figure 5.
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References

    1. Richter L.; de Graaf C.; Sieghart W.; Varagic Z.; Morzinger M.; de Esch I. J.; Ecker G. F.; Ernst M. Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands. Nat. Chem. Biol. 2012, 8, 455–464. - PMC - PubMed
    1. Forrest L. R.; Zhang Y. W.; Jacobs M. T.; Gesmonde J.; Xie L.; Honig B. H.; Rudnick G. Mechanism for alternating access in neurotransmitter transporters. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 10338–10343. - PMC - PubMed
    1. Kristensen A. S.; Andersen J.; Jorgensen T. N.; Sorensen L.; Eriksen J.; Loland C. J.; Stromgaard K.; Gether U. SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol. Rev. 2011, 63, 585–640. - PubMed
    1. Clausen R. P.; Frolund B.; Larsson O. M.; Schousboe A.; Krogsgaard-Larsen P.; White H. S. A novel selective gamma-aminobutyric acid transport inhibitor demonstrates a functional role for GABA transporter subtype GAT2/BGT-1 in the CNS. Neurochem. Int. 2006, 48, 637–642. - PubMed
    1. Borden L. A. GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem. Int. 1996, 29, 335–356. - PubMed

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