Tuesday, June 1, 2010


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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.

(Photo: OSU)

Ohio State University


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Observations of how the youngest-known neutron star has cooled over the past decade are giving astronomers new insights into the interior of these super-dense dead stars.

Dr Wynn Ho presented the findings on Thursday April 15th at the RAS National Astronomy Meeting in Glasgow.

Dr Ho, of the University of Southampton, and Dr Craig Heinke, of the University of Alberta in Canada, measured the temperature of the neutron star in the Cassiopeia A supernova remnant using data obtained by NASA’s Chandra X-ray Observatory between 2000 and 2009.

“This is the first time that astronomers have been able to watch a young neutron star cool steadily over time. Chandra has given us a snapshot of the temperature roughly every two years for the past decade and we have seen the temperature drop during that time by about 3%,” said Dr Ho.

Neutron stars are composed mostly of neutrons crushed together by gravity, compressed to over a million million times the density of lead. They are the dense cores of massive stars that have run out of nuclear fuel and collapsed in supernova explosions. The Cassiopeia A supernova explosion, likely to have taken place around 1680, would have heated the neutron star to temperatures of billions of degrees, from which it has cooled down to a temperature of about two million degrees Celsius.

“Young neutron stars cool through the emission of high-energy neutrinos – particles similar to photons but which do not interact much with normal matter and therefore are very difficult to detect. Since most of the neutrinos are produced deep inside the star, we can use the observed temperature changes to probe what’s going on in the neutron star’s core. The structure of neutron stars determines how they cool, so this discovery will allow us to understand better what neutron stars are made of. Our observations of temperature variations already rule out some models for this cooling and has given us insights into the properties of matter that cannot be studied in laboratories on Earth,” said Dr Ho.

Initially, the core of the neutron star cools much more rapidly than the outer layers. After a few hundred years, equilibrium is reached and the whole interior cools at a uniform rate. At approximately 330 years old, the Cassiopeia A neutron star is near this cross-over age. If the cooling is only due to neutrino emission, there should be a steady decline in temperature. However, although

Dr Ho and Dr Heinke observed an overall steady trend over the 10 year period, there was a larger change around 2006 that suggests other processes may be active.

“The neutron star may not yet have relaxed into the steady cooling phase, or we could be seeing other processes going on. We don’t know whether the interior of a neutron star contains more exotic particles, such as quarks, or other states of matter, such as superfluids and superconductors. We hope that with more observations, we will be able to explain what is happening in the interior in much more detail,” said Dr Ho.

Dr Ho and Dr Heinke have submitted a paper on their discovery to the Astrophysical Journal.

(Photo: NASA/CXC/MIT/UMass Amherst/M.D.Stage et al.)

The Royal Astronomical Society


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A lightning researcher at the University of Bath has discovered that during thunderstorms, giant natural particle accelerators can form 40 km above the surface of the Earth.

Dr Martin Füllekrug from the University’s Department of Electronic & Electrical Engineering presented his new work on Wednesday 14 April at the Royal Astronomical Society National Astronomy Meeting (RAS NAM 2010) in Glasgow.

His findings show that when particularly intense lightning discharges in thunderstorms coincide with high-energy particles coming in from space (cosmic rays), nature provides the right conditions to form a giant particle accelerator above the thunderclouds.

The cosmic rays strip off electrons from air molecules and these electrons are accelerated upwards by the electric field of the lightning discharge. The free electrons and the lightning electric field then make up a natural particle accelerator.

The accelerated electrons then develop into a narrow particle beam which can propagate from the lowest level of the atmosphere (the troposphere), through the middle atmosphere and into near-Earth space, where the energetic electrons are trapped in the Earth’s radiation belt and can eventually cause problems for orbiting satellites.

These are energetic events and for the blink of an eye, the power of the electron beam can be as large as the power of a small nuclear power plant.

Dr Füllekrug explained: “The trick to determining the height of one of the natural particle accelerators is to use the radio waves emitted by the particle beam.”

These radio waves were predicted by his co-worker Dr Robert Roussel-Dupré using computer simulations at the Los Alamos National Laboratory supercomputer facility.

A team of European scientists, from Denmark, France, Spain and the UK helped to detect the intense lightning discharges in southern France which set up the particle accelerator.

They monitored the area above thunderstorms with video cameras and reported lightning discharges which were strong enough to produce transient airglows above thunderstorms known as sprites. A small fraction of these sprites were found to coincide with the particle beams.

The zone above thunderstorms has been a suspected natural particle accelerator since the Scottish physicist and Nobel Prize winner Charles Thomson Rees Wilson speculated about lightning discharges above these storms in 1925.

In the next few years five different planned space missions (the TARANIS, ASIM, CHIBIS, IBUKI and FIREFLY satellites) will be able to measure the energetic particle beams directly.

Dr Füllekrug commented: “It’s intriguing to see that nature creates particle accelerators just a few miles above our heads. Once these new missions study them in more detail from space we should get a far better idea of how they actually work.

“They provide a fascinating example of the interaction between the Earth and the wider Universe.”

(Photo: Oscar van der Velde, Universitat de Catalunya, Spain and Serge Soula, Laboratoire d'Aerologie, France)

University of Bath




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