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Pairwise structural comparison of tiagabine analogs gives new insights into their protein binding modes

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Tiagabine (Gabitril®) is a selective inhibitor of the human gamma-aminobutyric acid (GABA) transporter 1 (hGAT-1), a transport protein belonging to the family of neurotransmitter-sodium-symporters (NSS). It is a marketed drug, used for treatment of epilepsy. However, the molecular basis of protein-ligand interaction remains obscure due to the lack of a 3D structure of the target protein.

In order to identify activity-determining structural features of a series of tiagabine analogs taken from literature [13], we chose an approach combining traditional methods of molecular modeling with exhaustive sampling of docking poses, and a pairwise comparison of structural features and their respective bioactivity values.

We determined a common binding mode of tiagabine analogs, which is in nice agreement with literature [4]. Further, we were able to trace back considerable differences in inhibitory activities to distinct molecular attributes of the analogs.

Our study revealed the molecular explanation for the importance of a polar linker region and thus paves the way for subsequent screening efforts in the search for novel GAT-1 inhibitors.

References

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    Andersen KE, et al: Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates. J Med Chem. 1999, 42: 4281-4291. 10.1021/jm980492e.

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    Skovstrup , et al: Homology modelling of the GABA transporter and analysis of tiagabine binding. Chem Med Chem. 2010, 5: 986-1000.

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Correspondence to Barbara Zdrazil.

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Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Zdrazil, B., Jurik, A., Sitte, H.H. et al. Pairwise structural comparison of tiagabine analogs gives new insights into their protein binding modes. J Cheminform 5, P32 (2013) doi:10.1186/1758-2946-5-S1-P32

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Keywords

  • Structural Feature
  • Molecular Modeling
  • Binding Mode
  • Molecular Attribute
  • Linker Region