Study paves way for designing drugs with fewer side effects

Nagarajan Vaidehi
Nagarajan Vaidehi, Ph.D.
More than 30% of the major pharmaceuticals used today belong to a class of drugs that target G-protein coupled receptors (GPCRs). They include opioids as well as treatments for high blood pressure, type 2 diabetes, asthma, schizophrenia and many other serious conditions. These drugs are highly effective, but they can also produce side effects.
Thanks to a new study by City of Hope scientists just published in Proceedings of the National Academy of Sciences of the United States of America (PNAS), researchers may now be able to design GPCR drugs with minimal side effects.
The study was conducted by Manbir Sandhu, a Ph.D. student at the Irell & Manella Graduate School of Biological Sciences at City of Hope, under the supervision of Nagarajan Vaidehi, Ph.D., chair of the Department Computational and Quantitative Medicine within Beckman Research Institute of City of Hope.
GPCRs play a key role in cellular communication and signaling, and a GPCR drug works by targeting the function required to treat a particular condition — but because a single GPCR can perform other functions as well, side effects are produced.
For example, when someone is given an opioid-based drug for treating pain, this drug turns on the function of the opioid GPCR that modulates pain, but it also turns on another function that causes addiction.
That’s what was known about GPCRs before the study — but a key piece of information was missing that would enable drug manufacturers to reduce side effects.
“It was imperative to understand the mechanism of how a given GPCR conducts multiple functions in the cell,” said Vaidehi. “Once we knew that, it would lead to strategies to design drugs that affect one specific function of the target GPCR instead of all of its functions.”
Using physics-based computational methods and simulations, Vaidehi and Sandhu set out to discover that mechanism.
“What we found is that G-protein coupled receptors conduct their multiple functions by elaborately morphing their shape,” said Sandhu. “For example, when they modulate pain they take one shape, and when they cause addiction they take another shape. And we were able to precisely map the mechanism by which they modulate their shapes.”
In order to do his, Sandhu took a GPCR with a single function and engineered mutations to make it multifunctional. Then he took the multifunctional GPCR and was able to make it single function again. These engineered mutations were validated using spectroscopic experiments in live cells in collaboration with scientists at University of Minnesota.
“Manbir was the first one to show how this change in shape allows for dynamic modulation of function, and how certain receptors dynamically adapt to these shapes,” Vaidehi said. “Now we will be able to design a small molecule that targets only one function and no others.”
This finding is fundamental and can be applied to any type of drug design for any type of disease, including heart disease, neurodegenerative diseases, cancer, diabetes, schizophrenia and neurological disorders.
The study has drawn the attention of the pharmaceutical industry. Bristol-Myers Squibb and Boehringer Ingelheim are now using the models developed by Sandhu and Vaidehi to design a new generation of GPCR medications — ones that will greatly reduce side effects.