One drug, many targets: Finding molecular targets of an HIV drug used in cancer therapy

April 28, 2011

Researchers at the University of California, San Diego and Hunter College of the City University of New York (CUNY) have identified potential human molecular targets of the anti-HIV drug Nelfinavir, which may explain why the drug is also effective as a cancer therapy. Their study will be published in the online edition of PLoS Computational Biology on April 28.

Nelfinivir is a that prevents replication of the , but it has also been found to have a positive effect on a number of solid tumor types, and is currently in clinical trial as a . However, the mechanism of how the drug worked in humans was not clear.

The researchers discovered that Nelfinavir may interact with multiple human protein kinases – enzymes that modify other proteins and regulate the majority of cellular pathways. Protein kinases comprise approximately 2 percent of the human genome, and are important anti-cancer drug targets.

Surprisingly, the interactions between Nelfinavir and kinases are much weaker than those from more specific, rationally designed drugs, said Philip Bourne, PhD, professor of pharmacology at UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences. Bourne and colleagues suggest that it is the collective effect of these weak interactions that leads to the clinical efficacy of Nelfinavir.

The research team – Li Xie, PhD, from UC San Diego, Thomas Evangelidis, a former graduate student in Bourne's lab, now at the University of Manchester, and research scientist Lei Xie, PhD, now an associate professor at Hunter College, CUNY – combined a wide array of computational techniques to investigate the molecular mechanisms underlying Nelfinavir's observed anti-cancer effect.

While drug molecules are designed to bind to targeted proteins in order to achieve a therapeutic effect, small drug molecules can attach to off-target proteins with similar binding sites. The result may be unwanted side effects or, as in the case of Nelfinavir, a secondary and positive effect.

In the traditional strategy for drug discovery, scientists use high-throughput screening to find a suitable drug target. However, utilizing the RCSB Protein Data Bank – a worldwide repository of tens of thousands of three-dimensional protein structures – the UCSD researchers computationally compared binding sites in order to identify which proteins might be unintended targets.

Taking a single drug molecule, they looked at all proteins encoded by the human proteome to which that molecule could possibly bind.

"Computer analysis allows us to search for other binding sites that match a particular drug-binding site – like looking for other locks that can be opened by the same key," said Lei Xie.

While this novel computational pipeline is promising in fishing for drug targets from a significant portion of the human genome, Lei Xie cautioned that "it is especially challenging to validate weak drug-target interactions both computationally and experimentally." He added that modeling such drug actions requires that scientists find relevant proteins and then examine them in the context of a biological network, while at the same time simulating their cumulative effects.

"This is indeed challenging, but uncovering which protein receptors Nelfinavir binds to may help us design better anti-cancer drugs," said Bourne. "It is hard not to believe that this broad-based systems approach represents the future of drug discovery, at least as far as small-molecule drugs are concerned."

Related Stories

Recommended for you

Study suggests ending opioid epidemic will take years

July 20, 2017
The question of how to stem the nation's opioid epidemic now has a major detailed response. A new study chaired by University of Virginia School of Law Professor Richard Bonnie provides extensive recommendations for curbing ...

Team-based model reduces prescription opioid use among patients with chronic pain by 40 percent

July 17, 2017
A new, team-based, primary care model is decreasing prescription opioid use among patients with chronic pain by 40 percent, according to a new study out of Boston Medical Center's Grayken Center for Addiction Medicine, which ...

Private clinics' peddling of unproven stem cell treatments is unsafe and unethical

July 7, 2017
Stem cell science is an area of medical research that continues to offer great promise. But as this week's paper in Science Translational Medicine highlights, a growing number of clinics around the globe, including in Australia, ...

Popular heartburn drugs linked to higher death risk

July 4, 2017
Popular heartburn drugs called proton pump inhibitors (PPIs) have been linked to a variety of health problems, including serious kidney damage, bone fractures and dementia. Now, a new study from Washington University School ...

Most reproductive-age women using opioids also use another substance

June 30, 2017
The majority of reproductive-age and pregnant women who use opioids for non-medical purposes also use at least one other substance, ranging from nicotine or alcohol to cocaine, according to a University of Pittsburgh Graduate ...

At-risk chronic pain patients taper opioids successfully with psychological tools

June 28, 2017
Psychological support and new coping skills are helping patients at high risk of developing chronic pain and long-term, high-dose opioid use taper their opioids and rebuild their lives with activities that are meaningful ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.