G protein-coupled receptors (GPCRs) are the most prevalent gene family in the human genome. They are involved with everything from our sense of smell to immune system function to tumor growth. Unsurprisingly, GPCRs have been a hotbed for research and development. Of the 7,038 approved drugs analyzed for this blog post, I found that 29% of them target Class A (Rhodopsin-like) GPCRs, and 35% target any GPCR. In the spirit of Internet pop culture, I made a “quiz” to see if you can guess the top 10 receptors by their ligand’s chemical structure.
Double Your GPCR, Double Your Fun?
Understanding GPCR function could prove fruitful for treating numerous diseases. There is a split between scientists on whether or not dimerization is crucial for GPCR function. There are numerous technical overviews of the dimerization debate. Class C GPCRs undoubtedly function as dimers, although it’s not clear if Class A GPCRs function as monomers or in larger groups. The really interesting aspect to all of this is that when GPCRs come together to form homodimers (two identical proteins) or heterodimers (two nonidentical proteins), their binding sites could change. This change would open up a novel avenue for drug development. The question then becomes: which of these Class A GPCRs function in pairs of two or more? The International Union of Basic and Clinical Pharmacology (IUPHAR) created a starting point for several specific receptors.
Methods to Study Dimerization
Many studies from several years ago used in vitro methods to study GPCR dimerization; however, demonstrating colocalization in natural, living cells would be the most convincing evidence. A good approach to study in vivo dimerization is to use reporter molecules attached to each GPCR unit. The challenge with this method is that reporters could interfere with natural behavior, so using a small reporter molecule is ideal. Imagine using a basketball-sized GPS tag on a shark’s fin to track its movement—obviously that would interfere with its swimming. The same logic applies on the molecular level. Scientists have many tools at their disposal to explore in vivo interactions; some notable examples are listed below.
- Ligand binding – Armstrong and Strange, 2001
- Fluorescence resonance energy transfer (FRET) – Herrick-Davis et al. 2004
- Bioluminescence resonance energy transfer (BRET) – Angers et al., 2000
- Coimmunoprecipitation – Hebert et al. 1996
- Protein complementation assay (PCA) – Dixon et al. 2015
Top 10 GPCR Drug Targets
And the winner is… the acetylcholine receptor! Cute BuzzFeed-esque explanations for your score aside, the data deserve a little scientific explanation. For example, how accurate are these numbers? A 2006 study found that 26.8% of approved drugs target Class A GPCRs, which was an analysis of 1,357 FDA approved drugs. A small level of growth would be expected over a decade. Reports vary with estimates from 30–50% of total drugs targeting any class of GPCR. My estimate is at the lower end of this range, yet many of the higher estimates I found were either decades old or did not reference where or how the authors came to such a number. Here is the methodology I followed:
- I downloaded the data for this study from DrugBank.
- I then compared the drug targets to a detailed list from GPCRDB using Microsoft Excel.
In a similar vein to the graphic I created, Nature, Inpharmatica, and Pfizer put together a gorgeous infographic of the 186 human protein drug targets for FDA-approved oral drugs that is definitely worth checking out. Online resources like DrugBank, UniProt, and countless others are shining examples of the collaborative spirit of science. While the GPCR dimerization debate is ongoing, improved research tools will help scientists gain a clearer picture and enable future drug development.
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