UNC scientists discover how cells respond to common prescription drugs

Dissociation of G protein from drug-bound GPCR (orange) is captured in accelerated molecular dynamics simulations, starting from the bound (blue) to free state (red), with a trace of its C-terminal residue colored in a blue-white-red scale.
Photo Credit: Courtesy of Yinglong Miao, Anh T. N. Nguyen and Lauren May

Scientific Frontline: "At a Glance" Summary

• Main Discovery: Researchers at the UNC School of Medicine elucidated the precise molecular pathways by which G proteins dissociate from drug-activated G protein-coupled receptors (GPCRs) to initiate intracellular signaling.
• Methodology: The team utilized a computational technique known as "accelerated molecular dynamics" to simulate these protein interactions, with findings validated by experimental laboratory results in collaboration with Monash University.
• Specific Mechanism: The study, published in Proceedings of the National Academy of Sciences, demonstrated that specific small-molecule drug leads can bind to GPCRs with high selectivity and effectively slow down the G protein dissociation process.
• Key Statistic: This insight is highly relevant to pharmaceutical development, as GPCRs are the molecular targets for approximately one-third of all currently prescribed drugs.
• Significance/Future Application: Understanding this mechanism allows for the creation of precise medicines that fine-tune cell signaling—such as non-addictive treatments for neuropathic pain—by minimizing toxic side effects through selective receptor modulation.

Yinglong Miao  is one of the scientists making breakthrough in understanding the most widely used medicines at the molecular level.
Photo Credit: Courtesy of University of North Carolina at Chapel Hill

Scientists at the UNC School of Medicine have made a breakthrough in understanding how cells respond to some of the most widely used medicines at the molecular level.

Their study, published in the journal Proceedings of the National Academy of Sciences, demonstrates a very powerful computational method on how important proteins transmit cellular signals inside our bodies. Researchers hope these new findings could help create safer and more effective treatments for a wide range of conditions, ranging from heart disease to mental health disorders.

Many drugs work by targeting proteins called G protein-coupled receptors, which help cells respond to signals like hormones and neurotransmitters. These receptors are the focus of about one-third of all prescription drugs. Until now, scientists didn’t fully understand how “G proteins” break away from drug-activated receptors on the cell surface to continue the signaling process.

Through advanced computer simulations using an accelerated molecular dynamics method, UNC researchers enabled identification of G dissociation pathways and watched how these proteins broke away to carry signals deeper inside the cell. Their simulations matched real lab results and showed how a new type of drug compounds can slow down this breakaway process. This discovery shows a clearer picture of how medicines take effect inside our cells.

“Through international collaboration with a team at Monash University in Australia, we found these compounds could slow down the G protein dissociation in consistent simulations and experiments,” said Yinglong Miao, corresponding author and associate professor in the UNC School of Medicine’s pharmacology and computational medicine department. “The small molecules we studied were a special class of drug leads that can bind target GPCRs with high selectivity. Such compounds can avoid toxic side effects in patients. They are also candidates for treating neuropathic pain without causing drug addiction.”

This insight could help drug developers design more precise medicines that fine-tune cell signaling, potentially reducing side effects and improving treatment for a variety of health conditions.

Published in journal: Proceedings of the National Academy of Sciences

Title: Dissociation kinetics of G proteins from G protein–coupled receptors and effects of allosteric modulation

Authors: Jinan Wang, Anh T. N. Nguyen, Victor A. Adediwura, Cam Sinh Lu, Samantha M. McNeill, Manuela Jörg, Peter J. Scammells, Arthur Christopoulos, Lauren T. May, and Yinglong Miao

Source/Credit: University of North Carolina at Chapel Hill | Brittany Phillips

Reference Number: mbio011426_01

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