New understanding of cellular signaling could help design better drugs, Stanford study finds

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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 drug 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 cells that nutrients are nearby or communicate information sent by other cells. These messages symbolize a variety of signaling or pharmaceutical molecules. When one of these molecules binds to a GPCR, the GPCR changes shape — triggering many molecular changes within the cell.

Dror’s team investigated the relationship between these 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 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 activate the arrestin even more, 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.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Dynamic Duo: Antibiotics and Probiotics

Photograph of antibiotics.
Photograph of antibiotics, courtesy of sparktography via Creative Commons license.

When your cold or flu virus turns into a bacterial infection, taking antibiotics can seem like a miracle. You often start feeling better after just a day or two. Antibiotics work by killing bacteria or by stopping bacteria from multiplying. Antibiotics quickly make you feel better because the drug kills the majority of the targeted bacteria very quickly.

However antibiotics also kill beneficial bacteria and induce negative side effects — most commonly diarrhea, upset stomach, and vaginal yeast infection. For instance, antibiotics cause about one out of three people to get diarrhea by disrupting the balance of the intestinal flora, a collection of bacteria and other microorganisms in the digestive tract. This can result in an overgrowth of the Clostridium difficile bacteria that causes diarrhea. Similarly, antibiotics can disrupt the vaginal flora and cause an overgrowth of Candida yeasts to cause a yeast infection.

Probiotics are live bacteria, yeasts and other microbes intended to maintain or restore the supply of beneficial bacteria in the body, particularly the stomach and intestines. Probiotics are found naturally in certain foods, including yogurt, aged cheeses, kefir, miso, tempeh, and fermented cabbage. Dietary supplements are another common source of probiotics.

The use of probiotics to reduce antibiotic-induced side effects is now becoming more widely accepted by the medical profession. A recent study published in the Journal of the American Medical Association supports taking probiotics with antibiotics. A team of researchers from southern California combined and analyzed the results of 63 randomized controlled trials of probiotics for the prevention or treatment of antibiotic-associated diarrhea. The 11811 men and women included in this large combined study took a placebo or probiotics supplement along with their antibiotics. The people who took the probiotics were 42% less likely to develop diarrhea than those taking the placebo.

However, further research is needed to determine the most effective probiotics and dose. Of course it is also important to limit your use of antibiotics, using them only for bacterial infections when necessary.

For more information about using probiotics with antibiotics, check out my KQED Quest website.

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