GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors.

backgroundThe 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

methodsIn the present study, various GRID-independent molecular descriptor (GRIND) models have been developed to shed light on the 3D structural features of human GAT1 (hGAT1) inhibitors using nipecotic acid and N-diarylalkenyl piperidine analogs. Further, a binding hypothesis has been developed for the selected GAT1 antagonists by molecular docking inside the binding cavity of hGAT1 homology model.

resultsOur 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 DISCUSSION: Our docking results are strengthened by the structure activity relationship of the data series as well as by GRIND models, thus providing a significant structural basis for understanding the binding of antagonists, which may be useful for guiding the design of hGAT1 inhibitors.