Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Navigating in the ocean of molecules

11.08.2009
Tracking down new active agents for cancer or malaria treatment could soon become easier - thanks to a computer program with which researchers from the Max Planck Institute of Molecular Physiology in Dortmund aim to facilitate the search for suitable pharmaceutical substances.

The program, which is called Scaffold Hunter, acts as a tool for navigating chemical space. It generates maps of chemically-related structures and links them to biological activity, that is, to their potential to bind to proteins, in particular medically relevant proteins.

With the help of this new tool, the Max Planck scientists, together with colleagues from the universities of Frankfurt, Eindhoven and New Mexico, have identified substances that could provide possible candidates for the development of active agents for use in cancer treatment and malaria. (Nature Chemical Biology, June 28, 2009)

The dimensions of the chemical space, which contains the total number of all conceivable chemical structures, are unimaginable: it is estimated to contain up to 10160 different molecules. Written out in full, this figure would fill two lines of closely-spaced numbers on a typed page. However, only some of these - 1060 molecules according to the estimates - are potential active agents. Identifying these islands of biological activity in the ocean of all potential compounds is not an easy task.

"Organic synthesis cannot gauge the chemical space in its entirety," explains Stefan Wetzel, a researcher from Herbert Waldmann's group at the Max Planck Institute of Molecular Physiology in Dortmund. Chemists cannot cook up all possible compounds to test them. Therefore, the researchers have developed this navigation system to help them steer their way through this sea of possibilities. The program Scaffold Hunter generates a map of the chemical space based on structural criteria and uses it to identify biologically active compounds, e.g. natural substances. The program can also be used to predict new candidate agents that do not occur in nature.

The scientists focus on the medically relevant section of the chemical space, in which molecules contain ring-shaped structures. To do this, they reduce the molecules to their characteristic scaffolds. Scaffold Hunter then orders these structures in a kind of family tree based on their similarities: the program assigns smaller 'parent' scaffolds to each scaffold by gradually removing rings from the original 'child' scaffold. This generates innumerable parent-child relationships - structurally related molecules of varying complexity. The advantage lies in the fact that chemically similar compounds are very likely to display similar biological activity.

"These structurally-based lineages form the branches of the tree," explains Stefan Wetzel: "With the help of Scaffold Hunter we move along the branches from complex to increasingly simple structures which may be similar in their effect." Thus, the researchers identify structurally simple scaffolds with promising characteristics as the starting point in the quest for new active agents: chemists can then vary the scaffolds with different appendages to synthesize the optimal active agent. Scaffold Hunter can also be used to predict bioactive molecules that do not arise in nature but are very likely to display similar activity to related natural molecules, as the program also creates and visualizes virtual scaffolds. The researchers immediately demonstrated how efficiently the program works by discovering new inhibitors of pyruvate kinase. The inhibition of this enzyme is seen as a promising approach to the treatment of cancer and malaria.

An even more detailed search can be carried out if the scientist can enter information about biological activity - if available - at the beginning of the navigation process. In this case, Scaffold Hunter only links the scaffolds that are known to display the same biological activity to the branches. As a result, these branches are very likely to bear fruit: active substances are probably also located in the branches between the substances whose biological activity is already known. "In this way, we tracked down new inhibitors for 2-lipoxygenase and the oestrogen receptor alpha," says Steffen Renner, a former researcher at the Max Planck Institute and now an employee of the Novartis pharmaceutical concern. 5-lipoxygenase is a target protein in the treatment of inflammation and bladder cancer, while the oestrogen receptor alpha is an important starting point in the treatment of breast cancer.

"Scaffold Hunter is a key technological tool with innumerable possible applications," says Stefan Wetzel. "The program was consciously designed in a very user-friendly way so that non-experts can use it to analyse their data themselves," he adds. The researchers have made Scaffold Hunter available free of charge on the Internet. The source code can also be obtained: advanced users can thus adapt the program to their requirements and embark on more targeted explorations of the chemical space.

Original work:

Renner S, van Otterlo WAL, Dominguez Seoane M, Möcklinghoff S, Hofmann B, Wetzel S, Schuffenhauer A, Ertl P, Oprea TI, Steinhilber D, Brunsveld L, Rauh D, Waldmann H

Bioactivity-Guided Mapping and Navigation of Chemical Space

Nature Chemical Biology

DOI: 10.1038/nchembio.187, June 28, 2009

Wetzel S, Klein K, Renner S, Rauh D, Oprea TI, Mutzel P, Waldmann H

Interactive Exploration of Chemical Space with Scaffold Hunter

Nature Chemical Biology

DOI: 10.1038/nchembio.188, June 28, 2009

Stefan Wetzel | EurekAlert!
Further information:
http://www.mpi-dortmund.de

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>