The GABAB receptor (GABAB-R) is a heterodimeric class C G protein-coupled receptor comprised of the GABAB1a/b and GABAB2 subunits. The endogenous orthosteric agonist γ-amino-butyric acid (GABA) binds within the extracellular Venus flytrap (VFT) domain of the GABAB1a/b subunit. The receptor is associated with numerous neurological and neuropsychiatric disorders including learning and memory deficits, depression and anxiety, addiction and epilepsy, and is an interesting target for new drug

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... ment. Ligand- and structure-based virtual screening (VS) are used to identify hits in preclinical drug discovery. In the present study, we have evaluated classical ligand-based in silico methods, fingerprinting and pharmacophore mapping and structure-based in silico methods, structure-based pharmacophores, docking and scoring, and linear interaction approximation (LIA) for their aptitude to identify orthosteric GABAB-R compounds. Our results show that the limited number of active compounds and their high structural similarity complicate the use of ligand-based methods. However, by combining ligand-based methods with different structure-based methods active compounds were identified in front of DUDE-E decoys and the number of false positives was reduced, indicating that novel orthosteric GABAB-R compounds may be identified by a combination of ligand-based and structure-based in silico methods.