Results Promising for Computational Methods For Drug Development

New research, led by a Virginia Tech chemist, may someday help natural-products chemists decrease by years the amount of time it takes for the development of certain types of medicinal drugs. The research by T. Daniel Crawford, associate professor of chemistry, involves computations of optical rotation angles on chiral—non-superimposable—molecules. The research titled, "The Current State of ‘Ab Initio’ Calculations of Optical Rotation and Electronic Circular Dichcoism Spectra," appeared recently as the cover article in The Journal of Physical Chemistry A.

Many chiral molecules are important for medical treatment for illnesses ranging from acid-reflux to cancer. The term “chiral” means that two mirror images of a molecule cannot be superimposed onto each other. In other words, some are “left-handed” and some are “right-handed.”

“Most drugs have this handedness property,” Crawford says, “and for many of these drugs, even though both hands can cause a reaction, it is a situation where one hand does a good thing and one does a bad thing.” He used thalidomide as an example. A mixture of both hands of the drug was used in the late 1950s and early 1960s to treat morning sickness in pregnant women. Later studies revealed that, while one of the two hands acted as the desired sedative, the other hand was found to cause significant birth defects. Thalidomide was never approved by the FDA in the United States and was eventually taken off the market in Europe.

For chemists, therefore, it is often vital to determine which hand of a molecule they are using. In other words, when you have a sample of a chiral molecule, how do you distinguish between the left and right hand"

This is where a technique called polarimetry comes in to play. By shooting plane-polarized light through a sample of one hand, the chiral molecule in question will rotate to a characteristic angle either clockwise or counterclockwise, and the two hands of a chiral molecule produce opposite rotations.

“So if we figure out the direction and rotation of the light or each hand, we have a frame of reference for determining whether we have the left or right hand of a molecule,” Crawford says.

The problem with this method is that synthesizing the two hands of chiral molecules is often extremely time consuming. “It can take anywhere from weeks to years,” Crawford says.

Crawford’s research applies the theory of quantum mechanics to devise computational methods in order to eliminate having to create a synthetic molecule. “The hope is that this will allow us to calculate things like optical rotation very accurately,” he says. “So when an organic chemist has a molecule and doesn’t know if it is left- or right-handed, we can calculate that directly on the computer.”

Crawford says the ultimate goal in his research is to be able to provide organic chemists with computational tools to determine the handedness of a particular molecule they are working with. He said that such tools could speed up the drug development process by years.

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R.I. Physicists Use Big Computers To Gain Knowledge of Particles

What if, before designing a car, an engineer could use physical knowledge of atomic particles to design materials and know exactly how they would react in a collision? What if fundamental physical equations that predict how those particles will behave in various energy states (cold, heat, stress) could be used to design spacecraft? To solve the physics equations that will lead to the engineering designs of tomorrow, physicists at the University of Rhode Island are investigating the fundamental quantum mechanics of particles using computers from SGI.

The SGI Altix system, installed in August, is used by the Physics Department to solve one of the basic equations of quantum mechanics, the Schrodinger equation,which describes how matter behaves at the atomic scale. While the equationhas been solved in several simple cases, SGI Altix technology was chosen because systems involving more than two or three particles cannot bedirectly solved, and require instead the use of computationally intensive numerical methods.

"We selected the Altix because of the speed of the connectivity of the various nodes, the speed of the exchange of information between the nodes,the speed of the individual processors, and the flexibility that that offers," says Peter Nightingale, professor of physics, University ofRhode Island. "That is important because a lot of what we do involves linear algebra with matrices, and the matrices tend to be spread out over different nodes. There is communication necessary to do a coordinated calculation for a matrix that is spread out over these systems. It's the speed of that communication that really is a bottleneck at times. Our cluster system was simply becoming unreliable and the SGI Altix offers muchstronger connectivity and therefore we are able to do bigger calculations faster, which require a lot of compute power."

Purchased in July through James River Technical, Inc. (JRTI), SGI's exclusive higher education reseller, the SGI Altix 350, with 10Intel Itanium 2 processors running Novell SUSE Linux Enterprise Server 9, is connected to the older cluster as well as to numerous desktops in the Physics Department. The SGI Altix system is also connected to the Internet, allowing anyone with access to use it, typically students who log in from home.

The SGI Altix 350 system will be used by Nightingale and his students as part of an ongoing program, supported by the National Science Foundation (NSF), to study the behavior of small van der Waals complexes and to develop their own applications. These van der Waals systems consist of a small number of weakly interacting atoms, and the research addresses the fundamental problem of solving the Schrodinger equation for these systems. The University of Rhode Island researchers will develop new Monte Carlo methods to solve this equation, and the SGI Altix system will supply the power to speed up study of these particle systems and compare them with experiments.

As Nightingale explains, the development of these methodsalso has implications for future engineering design.

"The energies of ground and excited states tell us about how the particles interact with each other, but what is not really known is how complicated systems interact, what the strength of the interaction is, as the distance changes," adds Nightingale. "For instance, if you can accurately predict where the energy levels are, you can figure out what the interactions between the particles are and that is important for all sorts of applications. Ultimately, and we may not be there for quite a while, the idea is to write down these fundamental physical equations and then designmaterials on the basis of the fundamental properties of this material. Right now, engineers design products based on what are called phenomenological models, which are a mixture of things that are known, things that are guessed, and things that are measured. But it would be much more elegant if you could start from fundamental physics, from the Schrodinger equation, and on the basis of that predict how your car will behave in a collision, for example. That's quite a stretch, but that's the ultimate goal."



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