Researchers at the Centre for Genomic Regulation (CRG) have developed a new way of identifying new druggable sites on a family of proteins that could help design treatments with fewer side effects for a very wide range of conditions from heart disease to depression.
The method allows scientists to create detailed functional maps of G protein-coupled receptors, or GPCRs, a type of protein that sits on the surface of a cell. One in three regulatory-approved drugs worldwide target this family of proteins
There are 800 different types of GPCRs. Adrenaline, histamine and serotonin all rely on different variants to transmit signals from the outside world into the cell. They are also targets for beta blockers, antihistamines, opioids and asthma inhalers.
However, each GPCR's architecture is similar enough that a drug designed to hit one target often hits others too, causing unintended and unwanted side effects. Designing a drug that reliably prefers one over the other has been largely a matter of luck.
A study led by Taylor Mighell and Ben Lehner and published today in Nature Structural & Molecular Biology shows a new way of building a map of beta-2 adrenergic receptor, a GPCR which tells cells to relax airways. It is a drug target for asthma and COPD inhalers such as salbutamol and salmeterol.
They built it by creating thousands of variants of the protein, swapping one building block for another. They synthesised 7,500 versions in total, each of which was put into a human cell and tested with different drug doses and other parameters, producing more than 150,000 measurements for a single receptor.
The resulting data showed new potential drug targets that have been previously hidden from sight. Many of the regions have adjustable positions that can be altered to finetune the behaviour of the receptor, which in turn could allow for more precise control of cellular response.
To test whether the method works beyond a single receptor, the team applied it to a second protein involved in regulating water in the kidneys and found comparable results. The research team's long-term ambition is to build similar maps for many more members of the GPCR family.
The authors describe the work as the beginning of a new era of GPCR drug discovery. The first chapter involved screening thousands of compounds to find ones that worked with little understanding of why.
Salmeterol, developed in the 1980s, is one example. It targets a region the new map predicts is important as a therapeutic target, though no one at the time knew why.
The second chapter, from the 1990s, involved designing drugs based on the receptor's three-dimensional structure, work that earned a Nobel Prize in 2012. The protein's shape helped understand where a drug can bind, but couldn't help predict what a drug will do once it binds.
The new method enables a "third era", where scientists can understand both the structure and the function of every part of the receptor. "You can have a perfect diagram of the working parts of a protein and still not know what happens when you change a component. Now, we have something closer to a manual than a diagram," concludes Dr. Mighell.
