An effective drug with minimal side effects — the dream of all drug companies, physicians and patients. But is it an impossible dream?
Perhaps not, in light of new research led by Ron Dror, PhD, an associate professor of computer science at Stanford. In collaboration with other researchers, Dror used computer simulations and lab experiments to better understand G-protein-coupled receptors, which are critical to drug development.
G-protein-coupled receptors (GPCRs) are involved in an incredible array of physiological processes in the human body, including vision, taste, smell, mood regulation and pain, to name just a few. As a result, GPCRs are the primary target for drugs — about 34 percent of all prescription pharmaceuticals currently on the market target them. Unfortunately, despite all of this research, many of the underlying mechanisms of how GPCRs function are still unclear.
We do know that GPCRs act like an inbox for biochemical messages, which alert the cell that nutrients are nearby or communicate information sent by other cells. When one of these messaging molecules binds to a GPCR, the GPCR changes shape — triggering molecular changes within the cell.
Dror’s team investigated the relationship between GPCRs and a key family of molecules inside cells called arrestins, which can be activated by GPCRS and can lead to unanticipated side effects from medications. Specifically, they sought to understand how GPCRs activate arrestin, so they can use this knowledge in the future to design drugs with fewer side effects.
“We want the good without the bad — more effective drugs with fewer dangerous side effects,” Dror said in a recent Stanford news release. “For GPCRs, that often boils down to whether or not the drug causes the GPCR to stimulate arrestin.”
Researchers know that a GPCR is composed of a long tail and a rounder core, which bind to distinct locations on the arrestin molecule. Based on past studies, it was believed that only the receptor’s tail activated the arrestin — causing it to change shape and begin signaling other molecules on its own.
However, Dror’s new study demonstrated that either the tail or core can activate arrestin, as recently reported in Nature. And the core and tail together can amp up activation of arrestin, Dror said.
Using this new understanding, the researchers hope in the future to design drugs that activate arrestin in a more selective way to reduce drug side effects.
Dror concluded in the release:
These behaviors are critical to drug effects, and this should help us in the next phase of our research as we try to learn more about the interplay of GPCRs and arrestins, and potentially, new drugs.
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