A Binding Mode Hypothesis of Tiagabine Confirms Liothyronine Effect on γ‑Aminobutyric Acid Transporter 1 (GAT1)

Elevating
GABA levels in the synaptic cleft by inhibiting its reuptake
carrier GAT1 is an established approach for the treatment of CNS disorders
like epilepsy. With the increasing availability of crystal structures
of transmembrane transporters, structure-based approaches to elucidate
the molecular basis of ligand–transporter interaction also
become feasible. Experimental data guided docking of derivatives of
the GAT1 inhibitor tiagabine into a protein homology model of GAT1
allowed derivation of a common binding mode for this class of inhibitors
that is able to account for the distinct structure–activity
relationship pattern of the data set. Translating essential binding
features into a pharmacophore model followed by in silico screening
of the DrugBank identified liothyronine as a drug potentially exerting
a similar effect on GAT1. Experimental testing further confirmed the
GAT1 inhibiting properties of this thyroid hormone.