Five sets of ρ1 GABAC homology models were generated based on X-ray crystal structures of the acetylcholine binding protein (AChBP), the ion channel from Caenorhabditis elegans (GLIC), the ion channel from Erwinia chrysanthemi (ELIC), the homomeric GABAA β3 ion channel, and the homomeric α-subunit of glutamate-gated homopentameric chloride channel (GluCl). The GluCl based model was found to the represent the structure of ρ1 GABAC receptors. The GABA pose docked in the selected best model was confirmed by QM-polarized ligand docking and induced fit docking protocol, and used to study molecular interactions in the ρ1 GABA binding site. The potential interactions of identified residues are discussed. This study identified several residues with potential ligand interactions located on loops F and G with their side chain oriented toward the binding site such as Ser215 and Gln83. The partial agonists muscimol and imidazole-4-acetic acid (I4AA) were docked into the binding site of the most reliable ‘GABA bound’ homology model. The potency and efficacy of these partial agonists in activating recombinant ρ1 receptors were correlated with their docking results. The model predicts that muscimol resembles GABA in the docking pose with similar interactions. However, I4AA has a very different docking pose to GABA and was predicted by the model to form π–π stacking with aromatic residues in the orthosteric binding site. A set of TPMPA bound ρ1 homology models based on the GluClα ‘apo state’ template was built in order to study a competitive antagonist in the ρ1 orthosteric binding site. The results demonstrated the ability of our model to explain most experimental findings and predict potential roles of residues within the orthosteric binding site.