Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

Abstract

At least 120 non-olfactory G protein-coupled receptors in the human genome are ”orphans” for which endogenous ligands are unknown, and many have no selective ligands, hindering elucidation of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Yeast-based screens against GPR68 identified the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. Over 3000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators many of which were confirmed in functional assays. One potent GPR68 modulator—ogerin– suppressed recall in fear conditioning in wild-type, but not in GPR68 knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.

DREADDs for Neuroscientists

“…In terms of creating new DREADDs, we have described a generic platform wherein human GPCRs can be expressed in yeast with engineered selectable markers and chimeric G proteins (Armbruster et al, 2007; Dong et al, 2010) and have used this platform to express dozens of human GPCRs (Huang et al, 2015b). In theory it should be possible to create new DREADDs by directed molecular evolution of human GPCRs using the prior yeast-based platforms (Armbruster et al, 2007; Dong et al, 2010; Huang et al 2015c).…”

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

“…Indeed, the structural data allows a move from traditional high-throughput screening methods to cheaper and efficient virtual screening approaches for the identification of novel ligands. In the recent study Huang and colleagues have used homology models of the poor-characterized receptors, GPR68 and GPR65 for virtual screening and identified potent ligands (Huang et al 2015). A similar approach could be applied for FFA3 to find potent modulators for future pharmacological and modelling studies of the receptor.…”

Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

“…Although the ligands of the nonorphan receptors in this family are all peptides [ghrelin, growth hormone secretagogue receptor (Kojima et al, 1999); neurotensin, NTSR1 and NTSR2 (Tanaka et al, 1990;Vita et al, 1998); motilin, MLNR (Feighner et al, 1999); neuromedin U, NMUR1 and NMUR2 (Kojima et al, 2000;Bhattacharyya et al, 2004)], GPR39 has been reported to be a Zn 21 metal ion-sensing receptor (Holst et al, 2007 , have also been reported to activate GPR39 (Holst et al, 2007;Huang et al, 2015). GPR39 is widely expressed in several organs, including the gastrointestinal tract, pancreas, thyroid, brain, and others (Popovics and Stewart, 2011).…”