Pairwise structural comparison of tiagabine analogs gives new insights into their protein binding modes
Journal of Cheminformatics volume 5, Article number: P32 (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 [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 . 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.
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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 (Suppl 1), P32 (2013). https://doi.org/10.1186/1758-2946-5-S1-P32
- Structural Feature
- Molecular Modeling
- Binding Mode
- Molecular Attribute
- Linker Region