In Silico Methods for the Discovery of Orthosteric GABAB Receptor Compounds

Abstract

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 development. 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.

The GABAB Receptor—Structure, Ligand Binding and Drug Development

“…Additional mutational studies followed by radioligand binding assays showed that mutating Ser130 to Ala abolished binding of the antagonist CGP54626, while mutation of Ser153 were found to affect the affinity of various ligands differently and are thereby suggested to play a role in selectivity of GABA B ligand recognition [51]. For more details about ligand interactions in the orthosteric binding site, please see [36,[51][52][53]. Ligand interactions with residues located in LB2 seem to be restricted to agonists and high-affinity antagonists [36,52,53].…”

“…For more details about ligand interactions in the orthosteric binding site, please see [36,[51][52][53]. Ligand interactions with residues located in LB2 seem to be restricted to agonists and high-affinity antagonists [36,52,53]. Interactions with residues in both LB1 and LB2 are likely to be a requirement for activation, and cause the agonists to become buried within the closed receptor conformation (Figure 3).…”

“…Linking receptor interaction patterns to ligand activity and affinity has proven to be difficult, as highly similar compounds show similar receptor interaction patterns despite of different activity [36]. Larger and more bulky antagonists, like CGP54626 and CGP62349, are thought to prohibit the formation of a stable closed conformation by forming few and variable interactions with the LB2, likely as a result of the size compared to agonists (Figure 3) [36,52].…”

“…All ligands co-crystalized with the VFT are structural derivatives of GABA with an α-acid and a γ-amino group [36]. The α-acid and the γ-amino groups of co-crystalized ligands are stabilized by identical residual interactions in all X-ray crystal structures, independent of intrinsic ligand activity [36,52,53]. Linking receptor interaction patterns to ligand activity and affinity has proven to be difficult, as highly similar compounds show similar receptor interaction patterns despite of different activity [36].…”

In silico structure‐based design of GABAB receptor agonists using a combination of docking and QSAR

“…Several authors carried out in silico approaches like docking studies on homology models over the GABA B receptor before the crystal structure of GABA B was solved (Costantino, Macchiarulo, Guadix, & Pellicciari, ; Pirard, Carrupt et al., ; Pirard, Paquet et al., ). However, the crystal structure was reported in 2013 (Geng et al., ) and there have not been structure‐based Baclofen analogues design efforts since then, excluding the work reported by Sylte and co‐workers, recently published (Evenseth, Warszycki, Bojarski, Gabrielsen, & Sylte, ).…”