Discovering novel drugs to target
G-protein–coupled receptors

Each circle, or “leaf”, in the GPCR tree corresponds to a distinct GPCR, grouped according to sequence similarity.

Whenever we experience a happy feeling, a sweet smell or a bright light, we have our G-protein–coupled receptors, or GPCRs, to thank. A plethora of signals — odors, hormones, neurotransmitters and photons — exert their biological effect by activating GPCRs. Once activated by a signal, a GPCR engages a G protein that processes GTP to activate downstream players in the biological cascade.

Because of their functional importance, a host of drugs target GPCRs by mimicking a signal or blocking their signal-binding site. Most of these drugs, however, are available for only a small subset of GPCRs, while the majority of GPCRs remain untapped.

As part of a recent minireview series published in the Journal of Biological Chemistry and coordinated by editor Henrik Dohlman at the University of North Carolina at Chapel Hill, pioneering scientific experts in the field of GPCRs offer valuable insights into the challenges of targeting a wider variety of GPCRs as well as some very creative solutions to those challenges.

One of the challenges is the need for faster and more efficient ways to screen novel drugs. There are 800 members in the human GPCR superfamily, and the traditional screening method involves testing one receptor at a time, usually requiring a tailor-made, radio-labeled probe or assay. In the first minireview, researchers Bryan Roth and Wesley Kroeze at the University of North Carolina at Chapel Hill describe the various high-throughput screens they and others have developed to circumvent this challenge and test not one but hundreds of receptors at the same time. Facilitating this enormous task are novel tools, such as broad-spectrum assay readouts, sophisticated bioinformatics analysis and high-quality chemical libraries. Many of these tools are available free of charge to the scientific community to accelerate the discovery of new drug candidates.

The other big hurdle in GPCR-targeted drug discovery is enhancing the selectivity of the drug — that is, making sure that the drug regulates only the desired receptor and not any other receptor. One solution to this problem is identifying allosteric sites on the target receptor — sites different from the signal-binding sites — that can influence the activity of the protein. Drugs that bind to these allosteric sites may help regulate the activity of one type of receptor but not of another. The second minireview, by Patrick R. Gentry, Patrick Sexton and Arthur Christopoulos at the Monash University in Melbourne, Australia, describes the latest techniques, including recent advances in structural biology, that are being employed to identify molecules, both exogenous and endogenous, that can modulate these allosteric sites.

Crystal structures of GPCRs are instrumental in identifying novel allosteric sites. The third minireview, by Ali Jazayeri, Joao Dias and Fiona Marshall from Heptares Therapeutics Limited, reveals how recent technical advances are accelerating GPCR crystallography and the discovery of novel drugs. These advances include steps in protein purification and engineering as well as the use of computational programs that simulate docking a drug onto the crystal structure of the receptor and play matchmaker between drugs and candidate binding sites.

These insightful minireviews provide a quick glance into the enormous potential of GPCRs in drug discovery and for treating a variety of diseases and conditions including mood disorders and cardiovascular disease.

Sapeck Agrawal Sapeck Agrawal is a medical and science writer with a Ph.D. in molecular biology. For more stories, visit her blog.