PeerJ 2019
GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors.
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Background
The γ-aminobutyric acid (GABA) transporter GAT1 is involved in GABA transport across the biological membrane in and out of the synaptic cleft. The efficiency of this Na+ coupled GABA transport is regulated by an electrochemical gradient, which is directed inward under normal conditions. However, in certain pathophysiological situations, including strong depolarization or an imbalance in ion homeostasis, the GABA influx into the cytoplasm is increased by re-uptake transport mechanism. This mechanism may lead to extra removal of extracellular GABA which results in numerous neurological disorders such as epilepsy. Thus, small molecule inhibitors of GABA re-uptake may enhance GABA activity at the synaptic clefts.Results
Our results indicate that two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region at certain distances from each other play an important role in achieving high inhibitory potency against hGAT1. Our docking results elucidate the importance of the COOH group in hGAT1 antagonists by considering substitution of the COOH group with an isoxazol ring in compound 37, which subsequently leads to a three order of magnitude decrease in biological activity of 37 (IC50 = 38 µM) as compared to compound 1 (IC50 = 0.040 µM).