Novel computational approach developed to test antidotes for nerve agents

Researchers at Lawrence Livermore National Laboratory (CA, USA) are using supercomputers to form simulations potentially able to significantly speed up the process of candidate drug testing.

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A team of researchers from Lawrence Livermore National Laboratory (CA, USA) have developed a novel method to simulate the energy requirements for candidate drug molecules to permeate cell membranes, a system potentially capable of shortening compound testing by a matter of weeks by identifying in advance how readily they will enter target cells.

Timothy Carpenter, one of the researchers, explained: "Instead of having one [drug molecule] starting from one side of the membrane, you have it starting at a hundred different points through the membrane."

At each of these points, the simulation imposes an artificial force of differing degrees on the molecule, to keep it in place. It then measures the degree of fluctuations and movement of the molecules at each position, and can thus obtain the related energy levels, which can be stitched together to generate a progressive energy profile. The researchers can also, from here, calculate the diffusion rate of the compound, which they combine with the energy profile to determine the permeability rate.

The alternative to the program, which would be to run a single simulation for the duration it would take the compound to permeate the membrane, is very time consuming, as the chances of a compound getting through with a high energy barrier are lower.

Carpenter and colleagues will present their work at this week’s Biophysical Society’s 60th Annual Meeting in Los Angeles (CA, USA). The group is currently developing more permeable oxime-based compounds, which will act as treatments for nerve agents such as sarin gas. These compounds are classified by the United Nations as weapons of mass destruction, and act by interrupting the breakdown of acetylcholine. This results in eventual painful death by asphyxiation.

Currently available treatments for nerve agents consist of concurrently administered oxime compounds, typically pralidoxime and atropine, which are very effective once in the brain, but are stymied by poor penetration of the blood-brain barrier.

"The goal of the project was to see if we could develop or improve on the permeability of some of these classes of compounds," Carpenter stated. “"It raises the question of: if you have a drug that is half as effective but four times as permeable, is that a better option than what we have at the moment?"

Carpenter added that assessing a drug’s membrane permeability is a process that typically takes about 6 weeks from start to finish, but the team’s process can allow researchers to assess permeability in 16 hours. The simulations are run on Lawrence Livermore National Laboratory’s supercomputers, two of which are currently ranked in the top 20 of the fastest supercomputers in the world. Each set of 100 simulations takes about 100,000 computer hours, which is the equivalent of three years on a single quad-core laptop.

The team plans to continue their research into anti-nerve agents, while implementing their methods in other drug design programs.


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Stella Bennett

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