Featured Research

from universities, journals, and other organizations

Study paves way to design drugs aimed at multiple protein targets at once

Date:
December 12, 2012
Source:
University of North Carolina Health Care
Summary:
Pharmaceutical chemists had suggested that the objective of a drug hitting multiple targets simultaneously is impossible and unlikely to succeed. A new study shows how to efficiently and effectively make designer drugs that can do that.

This is Brian L. Roth, M.D., Ph.D., Michael J. Hooker Distinguished Professor of Pharmacology in the UNC School of Medicine, professor in the Division of Chemical Biology and Medicinal Chemistry in the UNC Eshelman School of Pharmacy, and director of the National Institute of Mental Health Psychoactive Drug Screening Program.
Credit: UNC School of Medicine

An international research collaboration led by scientists at the University of North Carolina School of Medicine and the University of Dundee, in the U.K., have developed a way to efficiently and effectively make designer drugs that hit multiple protein targets at once.

This accomplishment, described in the Dec. 13, 2012 issue of the journal Nature, may prove invaluable for developing drugs to treat many common human diseases such as diabetes, high blood pressure, obesity, cancer, schizophrenia, and bi-polar disorder.

These disorders are called complex diseases because each have a number of genetic and non-genetic influences that determine susceptibility, i.e., whether someone will get the disease or not.

"In terms of the genetics of schizophrenia we know there are likely hundreds of different genes that can influence the risk for disease and, because of that, there's likely no single gene and no one drug target that will be useful for treating it, like other common complex diseases," said study co-leader, Brian L. Roth, MD, PhD, Michael J. Hooker Distinguished Professor of Pharmacology in the UNC School of Medicine, professor in the Division of Chemical Biology and Medicinal Chemistry in the UNC Eshelman School of Pharmacy, and director of the National Institute of Mental Health Psychoactive Drug Screening Program.

In complex neuropsychiatric conditions, infectious diseases and cancer, Roth points out that for the past 20 years drug design has been selectively aimed at a single molecular target, but because these are complex diseases, the drugs are often ineffective and thus many never reach the market.

Moreover, a drug that acts on a single targeted protein may interact with many other proteins. These undesired interactions frequently cause toxicity and adverse effects.

"And so the realization has been that perhaps one way forward is to make drugs that hit collections of drug targets simultaneously. This paper provides a way to do that," Roth said.

The new way involves automated drug design by computer that takes advantage of large databases of drug-target interactions. The latter have been made public through Roth's lab at UNC and through other resources.

Basically, the researchers, also co-led by Andrew L. Hopkins, PhD in the Division of Biological Chemistry and Drug Discovery, College of Life Sciences, at the University of Dundee, in Scotland, used the power of computational chemistry to design drug compounds that were then synthesized by chemists, tested in experimental assays and validated in mouse models of human disease.

The study team experimentally tested 800 drug-target predictions of the computationally designed compounds; of these, 75 percent were confirmed in test-tube (in vitro) experiments.

Drug to target engagement also was confirmed in animal models of human disease. In a mouse model of attention deficit hyperactivity disorder (ADHD), mice missing a particular dopamine receptor engage in recurrent aberrant behaviors similar to what is seen in ADHD: distractibility and novelty seeking. "We created a compound that was predicted to prevent those recurrent behaviors and it worked quite well," Roth said.

The researchers then tested the compound in another mouse model where a particular enzyme for a brain neuropeptide is missing. Distractibility and novelty seeking also are behavioral features in these animals. And the drug had the same effect in those mice.

The new drug design process includes ensuring that compounds enter the brain by crossing the blood-brain barrier. These, too, were tested successfully in live animals.

According to Roth, pharmaceutical company chemists had suggested that the objective of a drug hitting multiple targets simultaneously is impossible and unlikely to succeed. "Here we show how to efficiently and effectively make designer drugs that can do that."


Story Source:

The above story is based on materials provided by University of North Carolina Health Care. Note: Materials may be edited for content and length.


Journal Reference:

  1. Jérémy Besnard, Gian Filippo Ruda, Vincent Setola, Keren Abecassis, Ramona M. Rodriguiz, Xi-Ping Huang, Suzanne Norval, Maria F. Sassano, Antony I. Shin, Lauren A. Webster, Frederick R. C. Simeons, Laste Stojanovski, Annik Prat, Nabil G. Seidah, Daniel B. Constam, G. Richard Bickerton, Kevin D. Read, William C. Wetsel, Ian H. Gilbert, Bryan L. Roth, Andrew L. Hopkins. Automated design of ligands to polypharmacological profiles. Nature, 2012; 492 (7428): 215 DOI: 10.1038/nature11691

Cite This Page:

University of North Carolina Health Care. "Study paves way to design drugs aimed at multiple protein targets at once." ScienceDaily. ScienceDaily, 12 December 2012. <www.sciencedaily.com/releases/2012/12/121212134058.htm>.
University of North Carolina Health Care. (2012, December 12). Study paves way to design drugs aimed at multiple protein targets at once. ScienceDaily. Retrieved April 20, 2014 from www.sciencedaily.com/releases/2012/12/121212134058.htm
University of North Carolina Health Care. "Study paves way to design drugs aimed at multiple protein targets at once." ScienceDaily. www.sciencedaily.com/releases/2012/12/121212134058.htm (accessed April 20, 2014).

Share This



More Health & Medicine News

Sunday, April 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Nine-Month-Old Baby Can't Open His Mouth

Nine-Month-Old Baby Can't Open His Mouth

Newsy (Apr. 19, 2014) — Nine-month-old Wyatt Scott was born with a rare disorder called congenital trismus, which prevents him from opening his mouth. Video provided by Newsy
Powered by NewsLook.com
'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) — In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Little Progress Made In Fighting Food Poisoning, CDC Says

Little Progress Made In Fighting Food Poisoning, CDC Says

Newsy (Apr. 18, 2014) — A new report shows rates of two foodborne infections increased in the U.S. in recent years, while salmonella actually dropped 9 percent. Video provided by Newsy
Powered by NewsLook.com
Scientists Create Stem Cells From Adult Skin Cells

Scientists Create Stem Cells From Adult Skin Cells

Newsy (Apr. 17, 2014) — The breakthrough could mean a cure for some serious diseases and even the possibility of human cloning, but it's all still a way off. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins