Ligand-guided homology modelling of the GABA(B2) subunit of the GABA(B) receptor

γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and disturbances in the GABAergic system have been implicated in numerous neurological and neuropsychiatric diseases. The GABA(B) receptor is a heterodimeric class C G protein-coupled receptor (GPCR) consisting of GABA(B1a/b) and GABA(B2) subunits. Two GABA(B) receptor ligand binding sites have been described, namely the orthosteric GABA binding site located in the extracellular GABA(B1) Venus fly trap domain and the allosteric binding site found in the GABA(B2) transmembrane domain. To date, the only experimentally solved three-dimensional structures of the GABA(B) receptor are of the Venus fly trap domain. GABA(B) receptor allosteric modulators, however, show great therapeutic potential, and elucidating the structure of the GABA(B2) transmembrane domain may lead to development of novel drugs and increased understanding of the allosteric mechanism of action. Despite the lack of x-ray crystal structures of the GABA(B2) transmembrane domain, multiple crystal structures belonging to other classes of GPCRs than class A have been released within the last years. More closely related template structures are now available for homology modelling of the GABA(B) receptor. Here, multiple homology models of the GABA(B2) subunit of the GABA(B) receptor have been constructed using templates from class A, B and C GPCRs, and docking of five clusters of positive allosteric modulators and decoys has been undertaken to select models that enrich the active compounds. Using this ligand-guided approach, eight GABA(B2) homology models have been chosen as possible structural representatives of the transmembrane domain of the GABA(B2) subunit. To the best of our knowledge, the present study is the first to describe homology modelling of the transmembrane domain of the GABA(B2) subunit and the docking of positive allosteric modulators in the receptor.