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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Innovative Computing Technique, Unprecedented Simulation Earns Livermore Team Gordon Bell Prize

Using groundbreaking computational techniques, a team of scientists from Lawrence Livermore National Laboratory and IBM earned the 2007 Gordon Bell Prize for a first-of-a-kind simulation of Kelvin-Helmholtz instability in molten metals on BlueGene/L, the world’s fastest supercomputer.

By performing extremely large-scale molecular dynamics simulations, the team was able to study, for the first time, how a Kelvin-Helmholtz instability develops from atomic scale fluctuations into micron-scale vortices.

This has never been done before. We were able to observe this atom by atom. There was no time scale or length scale we couldn’t see,” says Jim Glosli, lead author on the winning entry titled “Extending Stability Beyond CPU Millennium: A Micron-Scale Simulation of Kelvin-Helmholtz Instability.”

Other team members were: Kyle Caspersen, David Richards, Robert Rudd and project leader Fred Streitz of LLNL; and John Gunnels of IBM.

The Kelvin-Helmholtz instability arises at the interface of fluids in shear flow and results in the formation of waves and vortices. Waves formed by Kelvin-Helmholtz (KH) instability are found in all manner of natural phenomena, such as waves on a windblown ocean, sand dunes and swirling cloud billows.

While Kelvin-Helmholtz instability has been thoroughly studied for years and its behavior is well understood at the macro-scale, scientists did not clearly understand how it evolves at the atomic scale until now.

The insights gained through simulation of this phenomenon are of interest to the National Nuclear Security Administration’s (NNSA) Stockpile Stewardship Program, the effort to ensure the safety security and reliability of the nation’s nuclear deterrent without nuclear testing.

Understanding how matter transitions from a continuous medium at macroscopic length scales to a discrete atomistic medium at the nanoscale has important implications for such laboratory research efforts as National Ignition Facility (NIF) laser fusion experiments and developing applications for nanotube technology.

“This was an important simulation for exploring the atomic origins of hydrodynamic phenomena, and hydrodynamics is at the heart of what we do at the Laboratory,” Glosli says. “We were trying to answer the question: how does the atomic scale feed into the hydrodynamic scale.”

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