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

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.


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Correspondence to Barbara Zdrazil.

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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).

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