Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New drug design technique could dramatically speed discovery process

14.04.2010
Scientists here are taking the trial and error out of drug design by using powerful computers to identify molecular structures that have the highest potential to serve as the basis for new medications.

Most drugs are designed to act on proteins that somehow malfunction in ways that lead to damage and disease in the body. The active ingredient in these medicines is typically a single molecule that can interact with a protein to stop its misbehavior.

Finding such a molecule, however, is not easy. It ideally will be shaped and configured in a way that allows it to bind with a protein on what are known as “hot spots” on the protein surface – and the more hot spots it binds to, the more potential it has to be therapeutic.

To accomplish this, many drug molecules are composed of units called fragments that are linked through chemical bonds. An ideal drug molecule for a specific protein disease target should be a combination of fragments that fit into each hot spot in the best possible way.

Previous methods to identify these molecules have emphasized searching for fragments that can attach to one hot spot at a time. Finding structures that attach to all of the required hot spots is tedious, time-consuming and error-prone.

Ohio State University researchers, however, have used computer simulations to identify molecular fragments that attach simultaneously to multiple hot spots on proteins. The technique is a new way to tackle the fragment-based design strategy.

“We use the massive computing power available to us to find only the good fragments and link them together,” said Chenglong Li, assistant professor of medicinal chemistry and pharmacognosy at Ohio State and senior author of a study detailing this work.

Li likens the molecular fragments to birds flying around in space, looking for food on the landscape: the protein surface. With this technique, he creates computer programs that allow these birds – or molecular fragments – to find the prime location for food, or the protein hot spots. The algorithm is originated from a computation technique called particle swarm optimization.

“Each bird can see the landscape individually, and it can sense other birds that inform each other about where the foods are,” Li said. “That’s how this method works. Each fragment is like a bird finding food on the landscape. And that’s how we place the fragments and obtain the best fragment combination for specific protein binding sites.”

Li verified that the technique works by comparing a molecular structure he designed to the molecular base of an existing cancer medication that targets a widely understood protein.

“My method reconstructed what pharmaceutical companies have already done,” he said. “In the future, we’ll apply this technique to protein targets for diseases that remain challenging to treat with currently available therapies.”

The research appears online and is scheduled for later print publication in the Journal of Computational Chemistry.

Li said this new computer modeling method of drug design has the potential to complement and increase efficiency of more time-consuming methods like nuclear magnetic resonance and X-ray crystallography. For example, he said, X-ray fragment crystallography can be hard to interpret because of “noise” created by fragments that don’t bind well to proteins.

With this new computer simulation technique, called multiple ligand simultaneous docking, Li instructs molecular fragments to interact with each other before the actual experimental trials, removing weak and “noisy” fragments so only the promising ones are left.

“They sense each other’s presence through molecular force. They suppress the noise and go exactly where they are supposed to go,” he said. “You find the right fragment in the right place, and it’s like fitting the right piece into a jigsaw puzzle.”

Before he can begin designing a molecule, Li must obtain information about a specific protein target, especially the protein structures. These details come from collaborators who have already mapped a target protein’s surface to pinpoint where the hot spots are, for example, through directed mutations or from databases.

Li starts the design process with molecular fragments that come from thousands of existing drugs already on the market. He creates a computer image of those molecules, and then chops them up into tiny pieces and creates a library of substructures to work with – typically more than a thousand possibilities.

That is where computational power comes into play.

“To search all of the possibilities of these molecular combinations and narrow them down, we need a massive computer,” he said. Li uses two clusters of multiple computers, one in Ohio State’s College of Pharmacy and the other in the Ohio Supercomputer Center, to complete the simulations.

The results of this computation create an initial molecular template that can serve as a blueprint for later stages of the drug discovery process. Medicinal chemists can assemble synthetic molecules based on these computer models, which can then be tested for their effectiveness against a given disease condition in a variety of research environments.

Li already has used this technique to identify molecules that bind to known cancer-causing proteins. He said the method can be applied to any protein that is a suspected cause of diseases of any kind, not just cancer.

This work was supported by the National Institutes of Health and faculty startup funds from the College of Pharmacy at Ohio State.

Huameng Li of Ohio State’s Biophysics Graduate Program is a co-author of the study.

Contact: Chenglong Li, (614) 247-8786; cli@pharmacy.ohio-state.edu
Written by Emily Caldwell, (614) 292-8310; caldwell.151@osu.edu

Chenglong Li | EurekAlert!
Further information:
http://www.ohio-state.edu

More articles from Life Sciences:

nachricht Antimicrobial substances identified in Komodo dragon blood
23.02.2017 | American Chemical Society

nachricht New Mechanisms of Gene Inactivation may prevent Aging and Cancer
23.02.2017 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

From rocks in Colorado, evidence of a 'chaotic solar system'

23.02.2017 | Physics and Astronomy

'Quartz' crystals at the Earth's core power its magnetic field

23.02.2017 | Earth Sciences

Antimicrobial substances identified in Komodo dragon blood

23.02.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>