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  • Open Access

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

  • 1Email author,
  • 1,
  • 2 and
  • 1
Journal of Cheminformatics20135 (Suppl 1) :P32

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

  • Published:

Keywords

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

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, Althanstrasse 14, Vienna, A-1090, Austria
(2)
Medical University of Vienna, Institute of Pharmacology, Vienna, A-1090, Austria

References

  1. Andersen KE, et al: The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. J Med Chem. 1993, 36: 1716-1725. 10.1021/jm00064a005.View ArticleGoogle Scholar
  2. Knutsen LJ, et al: Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. J Med Chem. 1999, 42: 3447-3462. 10.1021/jm981027k.View ArticleGoogle Scholar
  3. 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.View ArticleGoogle Scholar
  4. Skovstrup , et al: Homology modelling of the GABA transporter and analysis of tiagabine binding. Chem Med Chem. 2010, 5: 986-1000.View ArticleGoogle Scholar

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