Human gamma-aminobutyric acid (GABA) transporter 1 (hGAT-1) belongs to the neurotransmitter-sodium-symporter (NSS) family of transport proteins.  It has been a target for the design of antiepileptic therapeutics [1], with tiagabine (Gabitril�) being the only marketed drug. We implemented a computational approach to study the binding events taking place in hGAT1. The crystal structure of LeuT (Aquifex aeolicus) served as a template for homology modeling, tiagabine was docked into the binding site, and the membrane-embedded system was taken through a 30ns molecular dynamics (MD) simulation.The simulation yielded a stable protein which was then used for extracting ten representative snapshots out of the last 10ns of the trajectory. Subsequent docking studies of literature-retrieved tiagabine analogs into these relaxed protein structures revealed a common binding mode of the compounds, being able to explain differences in bioactivity values by distinctive structural features.This is the first step toward understanding subtype-selectivity of GABA transporters.The computational results presented have been achieved in part using the Vienna Scientific Cluster (VSC). We acknowledge financial support provided by the Austrian Science Fund, grants F03502 and W1232. [1] Pall�, A., Simon, A., Bencsura, A., H�ja, L. & Kardos, J. Substrate-Na+ complex formation: coupling mechanism for gamma-aminobutyrate symporters. Biochem. Biophys. Res. Commun 385, 210-214 (2009).

Molecular modeling studies of the human GABA transporter 1: Insights into binding events of Tiagabine analogs

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.