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 [1-3], 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
- 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. doi: 10.1021/jm00064a005. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1021/jm981027k. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1021/jm980492e. [DOI] [PubMed] [Google Scholar]
- Skovstrup. et al. Homology modelling of the GABA transporter and analysis of tiagabine binding. Chem Med Chem. 2010;5:986–1000. doi: 10.1002/cmdc.201000100. [DOI] [PubMed] [Google Scholar]