Major discovery reveals new understanding of how drugs work

Major discovery reveals new understanding of how drugs work

7 October 2016

A recent discovery by Monash researchers, published today in the journal Cell, has radically shifted our understanding of how one of the largest classes of drug targets work, potentially enabling better drug design.

Around 40% of the drugs currently on the market act on G protein-coupled receptors (“GPCRs”), which are found on almost all cells in the body. GPCRs sit on the surface of cells, responding to stimuli from the outside environment, including light, smell, and chemical molecules, and translating these into cellular responses.

In a study published today, Dr Sebastian Furness, Dr Denise Wootten and Professor Patrick Sexton of the Monash Institute of Pharmaceutical Sciences have revealed important new insights into what drives the response size of drugs at GPCRs, or their “efficacy”. Why do some drugs have a strong effect and others a weak one?

To answer this question, they looked at variants of the hormone calcitonin, an important regulator of calcium levels that helps prevent abnormal breakdown of bones.

“Both salmon and human calcitonin are used to treat bone disorders such as osteoporosis and Paget’s disease. However, salmon calcitonin binds to the receptor more readily than the human calcitonin. Because of that, you’d expect human calcitonin to have a weaker effect. But that’s not the case: salmon calcitonin and human calcitonin actually produce a similar cellular response. We wanted to find out why that was,” said Doctor Furness.

“We’ve known for some time that GPCRs move about and change their shapes, or their ‘conformation’. One of the ways drugs work is by stabilising a GPCR’s conformation. In doing so, they initiate an interaction between the receptor, which is on the surface of the cell, and the proteins inside the cell that drive cellular response, or the ‘effectors’.  This is what we’re referring to when we talk about the effect of a drug,” he said.

“Different drugs acting on the same GPCR can stabilise the receptor into different shapes, and the shape of the receptor dictates the effector with which it interacts. This explains how different drugs acting on the same GPCR can cause different cellular response: because they engage different effectors. But what it doesn’t explain is why both the salmon and human calcitonin have the same efficacy for the same cellular response when the human calcitonin has a weaker interaction with the receptor,” said Dr Furness.

“What we’ve shown for the first time is that, just as a drug can influence the shape of a GPCR, it can also directly influence the shape of an effector. In other words, the effector changes shape depending on the drug. So in this case the human calcitonin not only changes the shape of the GPCR to enable interaction with effectors, it also distinctly influences the shape of the effector. It shapes the effectors so that they can be activated more quickly to produce the same cellular response as occurs with salmon calcitonin. If you were looking solely at the GPCR, you would think that human calcitonin was less effective than salmon calcitonin, because it’s not binding as effectively to the receptor. What we’ve discovered is that this poorer binding is offset by the action human calcitonin has on the effector,” he said.

Dr Wootten explains that this observation opens up a new dimension in drug discovery.

“It gives researchers a new mechanism to exploit in their endeavour to design therapeutics that are more effective. It should mean that in the future drugs could be tailored not only to produce the desired therapeutic effect via stabilising the GPCR shape but also to control the magnitude of the response via stabilising the effector shape,” she said.

According to Professor Sexton, this could have significant outcomes for the economics of drug discovery.

“Developing new drugs is expensive. It takes years of research. And many drugs that look extremely promising in preclinical research fail to show therapeutic effects in human trials. Our discovery gives researchers a new tool, a new way to assess the efficacy of drugs that will enable them to more accurately determine the likelihood of success at an earlier stage,” said Professor Sexton.