Featured Research

from universities, journals, and other organizations

Many Receptor Models Used In Drug Design May Not Be Useful After All

Date:
October 7, 2008
Source:
Leiden University
Summary:
It may very well be that models used for the design of new drugs have to be regarded as impractical. Scientists have elucidated the structure of the adenosine A2A receptor, one of caffeine's main targets in the body and a key player in Parkinson's.

It may very well be that models used for the design of new drugs have to be regarded as impractical. This is the sobering though important conclusion of the work of two Leiden University scientists published in Science.

Together with an expert team at the Scripps Institute (La Jolla) led by crystallographer Ray Stevens, Ad IJzerman, head of the division of medicinal chemistry at the Leiden/Amsterdam Center for Drug Research, and postdoctoral fellow Rob Lane worked on the structure elucidation of this protein, which is one of caffeine's main targets in the human body, and a key player in Parkinson's disease.

Fatty

Obtaining a crystal structure of a receptor bound to a drug is by far the best way to learn and appreciate how drugs actually work. "For decades scientists from all over the world have struggled to get the crystal structure of this type of G protein-coupled receptor", IJzerman explains. "These arduous attempts are easily understood when one takes into account that the whole family of these proteins are the targets for almost half of the medicines that are available in the pharmacy shop. It seemed an impossible task, since these proteins are in the cell wall, which means they are in a fatty environment, and are fatty themselves. We all know that fat does not crystallize easily."

Fusion product

The scientists in California had found an elegant solution for this problem though. They coupled the receptor protein to another protein that, in contrast, crystallizes easily, and managed to obtain tiny crystals of the fusion product. That was sufficient to crack the architectural code of the protein, for which very advanced crystallization equipment was used. In fact, something similar had worked for yet another receptor, but this time it was an adenosine receptor's turn.

These receptors are at the core of the research in the division of medicinal chemistry of the Leiden/Amsterdam Center for Drug Research, and that's exactly why the American colleagues turned to the Leiden group. Forces were joined, and that's how the receptor constructs were characterized biochemically and pharmacologically, while at the same time the crystallization trials were ongoing across the Atlantic.

Supercaffeine

By the end of June 2008 the first crystals of suitable quality had been obtained and analyzed. That led to a big surprise that will undoubtedly have tremendous implications for the pharmaceutical industry. "The binding site for drugs on this receptor is very different from the one that had been found on two other receptors that we currently know the crystal structure of", says Rob Lane, asked for comments. "In the adenosine A2A receptor a small molecule, prosaically called ZM241385, is co-crystallized. This compound has high affinity for the receptor, and therefore it is best described as some sort of 'supercaffeine', a type of molecule that we had worked on in Leiden before." With some degree of understatement, Lane continues: "The drug is in a very different position than was expected on the basis of the other crystal structures. And there's the rub; almost everybody in the world of drug design has so far used receptor models that may not be so useful at all. That is the sobering and at the same time important discovery we made."

This study was supported by the Dutch Top Institute Pharma


Story Source:

The above story is based on materials provided by Leiden University. Note: Materials may be edited for content and length.


Cite This Page:

Leiden University. "Many Receptor Models Used In Drug Design May Not Be Useful After All." ScienceDaily. ScienceDaily, 7 October 2008. <www.sciencedaily.com/releases/2008/10/081002204433.htm>.
Leiden University. (2008, October 7). Many Receptor Models Used In Drug Design May Not Be Useful After All. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2008/10/081002204433.htm
Leiden University. "Many Receptor Models Used In Drug Design May Not Be Useful After All." ScienceDaily. www.sciencedaily.com/releases/2008/10/081002204433.htm (accessed October 20, 2014).

Share This



More Health & Medicine News

Monday, October 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Microneedle Patch Promises Painless Pricks

Microneedle Patch Promises Painless Pricks

Reuters - Innovations Video Online (Oct. 18, 2014) Researchers at The National University of Singapore have invented a new microneedle patch that could offer a faster and less painful delivery of drugs such as insulin and painkillers. Video provided by Reuters
Powered by NewsLook.com
Raw: Nurse Nina Pham Arrives in Maryland

Raw: Nurse Nina Pham Arrives in Maryland

AP (Oct. 17, 2014) The first nurse to be diagnosed with Ebola at a Dallas hospital walked down the stairs of an executive jet into an ambulance at an airport in Frederick, Maryland, on Thursday. Pham will be treated at the National Institutes of Health. (Oct. 16) Video provided by AP
Powered by NewsLook.com
Raw: Cruise Ship Returns to US Over Ebola Fears

Raw: Cruise Ship Returns to US Over Ebola Fears

AP (Oct. 17, 2014) A Caribbean cruise ship carrying a Dallas health care worker who is being monitored for signs of the Ebola virus is heading back to Texas, US, after being refused permission to dock in Cozumel, Mexico. (Oct. 17) Video provided by AP
Powered by NewsLook.com
Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

Spanish Govt: Four Suspected Ebola Cases in Spain Test Negative

AFP (Oct. 17, 2014) All four suspected Ebola cases admitted to hospitals in Spain on Thursday have tested negative for the deadly virus in a first round of tests, the government said Friday. Duration: 00:55 Video provided by AFP
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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