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 [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.