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Enhancing the disease-fighting power of drugs

Do you ever think about how medicines actually alleviate pain or cure disease? Curing is a complex process and involves understanding how various proteins found on the surface of human body cells convert external stimuli into biological signals within the cell.

G protein-coupled Receptors. Image courtesy Marta Filizola.

"Membrane proteins are protein molecules embedded in the cell membrane surface and they play a major role in mediating the effect of drugs,” explains Marta Filizola, an associate professor of structural and chemical biology at the Mount Sinai School of Medicine in New York, US. Her laboratory work is focused on understanding the signaling processes mediated by certain cell surface membrane proteins called G protein-coupled receptors. These interact with about half of all drugs currently on the market. Without G protein-coupled receptors, medicines would not be effective because they would not know their way into the cell.

Yet the exact workings of the G protein-coupled receptors at the molecular level are still shrouded in mystery. There is much debate about what parts of these proteins are important and how other aspects, like their ability to assemble (or oligomerize) in the cell surface membrane, affect cell signaling. Important insights into how these proteins work at a molecular level earned the scientists who contributed to them the Nobel Prize in Chemistry in 2012.

Human k-opiod receptor. Image courtesy Wikimedia commons.

"G protein-coupled receptors have been reported to form oligomeric complexes in a variety of disease states," says Filizola. "I'm trying to find out how these protein complexes process cell signaling so that we can make drugs more specific and design more efficient medicines."

Filizola’s lab is placing particular focus on opioid receptors – a group of G protein-coupled receptors that respond to opioids, medications commonly used to relieve pain. Recent simulations, created on supercomputers at the Texas Advanced Computing Center (TACC), US are aimed at comprehending the fundamental mechanisms of the opioid receptor function. Filizola’s lab creates “movies” from the simulations that reveal the way the ever-evolving proteins interact with drug molecules and other proteins. These movies contribute to a molecular-level understanding of the mechanism of action of drugs at individual or oligomeric receptors. This information is used to create more efficient medications and to stop unpleasant side effects.

In a paper recently published in PLoS Computational BiologyFilizola examined how different drugs can change the shape of a prototypical G protein-coupled receptor, thus producing different biological responses. In another paper appearing in PLoS Computational Biologyresearchers presented a methodology to estimate the strength of interactions between G protein-coupled receptors. Filizola hopes the results of her simulations and other studies will help formulate new hypotheses on how drugs and protein receptors function, so scientists can work on creating effective drugs with minimal side effects. "Side effects are an important issue,” adds Filizola. “ We can develop the best pain curing medication ever, but if it causes an addiction then how good is it really?"

In addition to the Scientific Computing Facility at Mount Sinai, Filizola uses the Ranger supercomputer at TACC. " These aren't simulations you can run on your desktop. We have to observe the movements of the proteins for a long time and it’s easy to miss out on important aspects of the interactions," she explains. "Models are only approximations and the simulations involved are complex, but now we have access to more detailed structural information about G protein-coupled receptors and resources at TACC to help with the necessary computations.”

In the future, Filizola plans to extend her molecular dynamics simulations to even larger supramolecular complexes to understand cell signaling better. "Safer and effective drugs are a pressing need and we must address the complexities involved fast."

A versionof this article first appeared on the TACCwebsite.

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