Volume 5 Supplement 1

8th German Conference on Chemoinformatics: 26 CIC-Workshop

Open Access

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

  • Barbara Zdrazil1Email author,
  • Andreas Jurik1,
  • Harald H Sitte2 and
  • Gerhard F Ecker1
Journal of Cheminformatics20135(Suppl 1):P32

https://doi.org/10.1186/1758-2946-5-S1-P32

Published: 22 March 2013

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.

Authors’ Affiliations

(1)
Department of Medicinal Chemistry, University of Vienna
(2)
Medical University of Vienna, Institute of Pharmacology

References

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Copyright

© Zdrazil et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://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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