Featured Research

from universities, journals, and other organizations

New class of small molecules discovered through innovative chemistry

Date:
November 21, 2011
Source:
The Scripps Research Institute
Summary:
Inspired by natural products, scientists have now created a new class of small molecules with the potential to serve as a rich foundation for drug discovery.

Inspired by natural products, scientists on the Florida campus of The Scripps Research Institute have created a new class of small molecules with the potential to serve as a rich foundation for drug discovery.

Related Articles


Combining the power of synthetic chemistry with some advanced screening technologies, the new approach could eventually expand by millions the number of provocative synthetic compounds available to explore as potential drug candidates. This approach overcomes substantial molecular limitations associated with state-of-the-art approaches in small molecule synthesis and screening, which often serve as the foundation of current drug discovery efforts.

The study, led by Scripps Research Associate Professor Glenn Micalizio, was published November 20, 2011, in an advanced online edition of the journal Nature Chemistry.

To frame the significance of this advance, Micalizio explains that high-throughput screening is an important component of modern drug discovery. In high-throughput screening, diverse collections of molecules are evaluated en masse for potential function in a biological area of interest. In this process, success is critically dependent on the composition of the molecular collections under evaluation. Modern screening centers maintain a relatively static collection of molecules, the majority of which are commercially available materials that have structures unrelated to natural products -- molecules that are appreciated as validated leads for drug development.

"This divergence in structure between natural products and commercially available synthetics lies at the heart of our inquiry," said Micalizio. "Why should we limit discovery of therapeutic leads to compound collections that are influenced by concerns relating to commercial availability and compatibility with an artificial set of constraints associated with the structure of modern screening centers?"

To expand the compounds available for investigation, the scientists embraced an approach to structural diversity that mimics nature's engine for the discovery of molecules with biological function. This process, termed "oligomerization," is a modular means of assembling structures (akin to the way that letters are used in a sequence to provide words with meaning) where a small collection of monomeric units can deliver a vast collection of oligomeric products of varying length, structure, and function (like the diversity of words presented in a dictionary).

Coupling this technique with a synthetic design aimed at generating molecules that boast molecular features inspired by the structures of bioactive natural products (specifically, polyketide-derived natural products, which include erythromycin, FK-506, and epothilone), the scientists established a new chemical platform for the discovery of potential therapeutics.

Micalizio points out: "The importance of oligomerization to drive discovery is well appreciated in chemistry and biology, yet a means to realize this process as an entry to small molecule natural product-inspired structures has remained elusive. The crux of the problem is related to challenges associated with the control of shape for each member of a complex oligomer collection -- the central molecular feature that defines biological function."

"It is the stability associated with the shape of these new compounds that lies at the heart of the practical advance," he continued. "The unique features of this science now make possible the ability to synthesize large collections of diverse natural product-inspired structures that have predictable and stable three-dimensional shapes."

Micalizio said that the science described represents a first step toward revolutionizing discovery at the interface of chemistry, biology, and medicine by embracing nature's strategy for molecular discovery. Coupling this type of advance with modern screening technology that can handle the evaluation of large compound collections at low cost (such as work by Scripps Florida Professor Thomas Kodadek, a co-author of the new study), can dramatically enhance the future of pharmaceutically relevant science.

The potential of this vision was highlighted in the new study, in which a 160,000-member compound collection was employed to discover the first non-covalent small molecule ligand to the DNA binding domain of p53 -- an important transcription factor that regulates a variety of genes involved in cell cycle control and cell death.

The first author of the study, "A Biomimetic Polyketide-Inspired Approach to Small-Molecule Ligand Discovery," is Claudio Aquino of Scripps Research. In addition to Micalizio and Kodadek, other authors include Mohosin Sarkar, Michael J. Chalmers, and Kimberly Mendes.

The study was supported by the Fidelity Biosciences Research Initiative, The State of Florida (The Florida Funding Corporation), and the National Institutes of Health.


Story Source:

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


Journal Reference:

  1. Claudio Aquino, Mohosin Sarkar, Michael J. Chalmers, Kimberly Mendes, Thomas Kodadek, Glenn C. Micalizio. A biomimetic polyketide-inspired approach to small-molecule ligand discovery. Nature Chemistry, 2011; DOI: 10.1038/nchem.1200

Cite This Page:

The Scripps Research Institute. "New class of small molecules discovered through innovative chemistry." ScienceDaily. ScienceDaily, 21 November 2011. <www.sciencedaily.com/releases/2011/11/111120134706.htm>.
The Scripps Research Institute. (2011, November 21). New class of small molecules discovered through innovative chemistry. ScienceDaily. Retrieved October 30, 2014 from www.sciencedaily.com/releases/2011/11/111120134706.htm
The Scripps Research Institute. "New class of small molecules discovered through innovative chemistry." ScienceDaily. www.sciencedaily.com/releases/2011/11/111120134706.htm (accessed October 30, 2014).

Share This



More Plants & Animals News

Thursday, October 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Galapagos Tortoises Bounce Back, But Ecosystem Lags

Galapagos Tortoises Bounce Back, But Ecosystem Lags

Newsy (Oct. 29, 2014) The Galapagos tortoise has made a stupendous recovery from the brink of extinction to a population of more than 1,000. But it still faces threats. Video provided by Newsy
Powered by NewsLook.com
Can Drinking Milk Lead To Early Death?

Can Drinking Milk Lead To Early Death?

Newsy (Oct. 29, 2014) Researchers in Sweden released a study showing heavy milk drinkers face an increased mortality risk from a variety of causes. Video provided by Newsy
Powered by NewsLook.com
Obama: The US Will Not 'run and Hide' From Ebola

Obama: The US Will Not 'run and Hide' From Ebola

AP (Oct. 29, 2014) Surrounded by health care workers in the White House East Room, President Barack Obama said the U.S. will likely see additional Ebola cases in the weeks ahead. But he said the nation can't seal itself off in the fight against the disease. (Oct. 29) Video provided by AP
Powered by NewsLook.com
Oatmeal Healthy Recipes and Benefits

Oatmeal Healthy Recipes and Benefits

Buzz60 (Oct. 29, 2014) Oatmeal is a fantastic way to start your day. Whichever way you prepare them, oats provide your body with many health benefits. In celebration of National Oatmeal Day, Krystin Goodwin (@krystingoodwin) has a few recipe ideas, and tips on how to kickstart your day with this wholesome snack! Video provided by Buzz60
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


Plants & Animals

Earth & Climate

Fossils & Ruins

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