Major human gamma-aminobutyrate transporter: in silico prediction of substrate efficacy.

The inhibitory gamma-aminobutyric acid transporter subtype 1 (GAT1) maintains low resting synaptic GABA level, and is a potential target for antiepileptic drugs. Here we report a high scored binding mode that associates GABA with gating in a homology model of the human GAT1. Docking and molecular dynamics calculations recognize the amino function of GABA in the H-bonding state favoring TM1 and TM8 helix residues Y60 and S396, respectively. This ligand binding mode visibly ensures the passage of GABA and substrate inhibitors (R)-homo-beta-Pro, (R)-nipecotic acid, and guvacine. It might therefore represent the principle, sufficient for sorting out less-effective or non-GAT ligands such as beta-Pro, (S)-nipecotic acid, (R)-baclofen, Glu, and Leu.