Shoichet study sheds light on “dark” cell receptors, potential drug targets

More than a quarter of all drugs work by targeting one of a large family of proteins called G-protein-coupled receptors (GPCRs). Hundreds of different GPCRs are embedded in cell membranes, converting stimuli from the outside world—neurotransmitters, hormones, even light—into intracellular signals that can change cell behavior.

There are at least 120 such GPCRs whose roles in health and disease are not yet known—they are also called “orphan” or “dark” receptors. But scientists can infer that these receptors probably have significant functions because they are evolutionarily conserved: they are seen in creatures ranging from worms to humans.

In a paper published today in the journal Nature, co-senior-authored by UCSF School of Pharmacy faculty member Brian Shoichet, PhD, researchers demonstrate a generalizable approach to discovering precise molecular probes for orphan cell receptors, helping to reveal their biological functions and make them accessible as targets for new drug development.

The study by investigators in the Shoichet Lab, in collaboration with scientists at the University of North Carolina, demonstrated their approach, which combines computational modeling and physical screening methods. They discovered a small molecule (ligand) that selectively binds to and activates signaling by orphan G-protein-coupled receptor 68 (GPR68, also known as OGR1).

In mice, GPR68 is most abundant in the cells of certain brain regions, such as the hippocampus, but its function there had not been known. However, when the new probe molecule—dubbed ogerin (for OGR1 ligand)—was given to mice, they were much less likely to learn to fear a specific stimulus. Such fear conditioning is controlled by the hippocampus; in addition, ogerin had no effect on genetically modified mice that lacked those GPR68 receptors.

“The druggable genome is an iceberg that is mostly submerged,” said Shoichet, whose lab developed the computational method to screen more than 3.1 million molecules for potential activity on GPR68. “This paper illuminates a small piece of it, providing new reagents to modulate a previously dark, unreachable drug target. Just as important, the strategy should be useful to many other dark targets in the genome.”

Indeed, to demonstrate its general research applicability, the researchers also used their approach to find molecules that can activate GPR65, another orphan receptor.

The Nature study was co-lead-authored by Joel Karpiak, PhD, while he was a Chemistry and Chemical Biology graduate student in the Shoichet Lab, which is based in the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry.

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Researchers Shed Pharmacological Light On Formerly “Dark” Cellular Receptors