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Targeting a killer

Speed read
  • Malaria is a deadly disease, and current drugs are losing effectiveness
  • HPC-assisted drug discovery helps scientists find promising new drug candidates
  • Simulating the compounds’ interactions on a computer is far more efficient than lab testing

A mosquito lands on your skin and starts to bite. You slap it away, but it may already be too late. In many parts of the world, especially Africa, that mosquito may have already transferred the malaria parasite into your bloodstream.

Malaria kills millions every year, and current drugs are losing their effectiveness. Afrah Khairallah of Rhodes University turns to high-performance computers and bioinformatics to identify likely candidates for new drugs.

The parasite multiplies rapidly in the human liver and red blood cells, leading to fever, chills, headaches, and vomiting. If not treated promptly, it can lead to death. More than  200 million cases occur every year, and the World Health Organization concludes that one child dies from the disease every two minutes.

While drugs do exist, they aren’t without problems. As Afrah Khairallah– a bioinformatics PhD candidate at the Research Unit in Bioinformatics, Rhodes University– points out, current treatments require an upgrade. New, drug-resistant strains of malaria are appearing all the time, rendering current drugs useless.

“With malaria, the parasite develops resistance,” says Khairallah. “You give people the treatment, but they don’t respond well. The parasite doesn’t get cleared from the host’s system. We need to find alternative drugs or alternative metabolic targets.”

By keeping costs and resource allocation low, Khairallah believes that a bioinformatics approach can completely change the process of discovery for new malaria drugs. What’s more, she thinks there’s something to be said about the great equalizing effect of science.

Saving money saving lives

The problem with drug discovery in the lab is that it’s a slow process. To test a proposed compound, biochemists have to first physically synthesize it, and then run it through a gamut of inspections to discover its effectiveness. The bioinformatics route, especially when combined with high-performance computing (HPC), is far more efficient.

<strong>Malaria parasites</strong> are transmitted to human hosts by female mosquitoes. Infected people can become very sick, or even die. The emergence of drug-resistant parasites is turning back the clock on efforts to control the disease. Courtesy NIH/NIAID. “Bioinformatics is cost effective,” says Khairallah. “We screen thousands of compounds with the help of HPC. This saves time and resources, especially in Africa. Some of the calculations we do, like the screening of the compounds or the quantum calculations we need, are expensive in terms of time and money. HPC allows us to accelerate the process. Thus we can screen thousands of compounds in a day.”

Khairallah states that this rigorous process starts with looking at the current literature. She identifies a certain metabolic pathway– or a specific sequence of chemical reactions – that’s  important to the malaria parasite’s survival. She then selects enzymes in this pathway to analyze.

“We focused on one malaria enzyme,” says Khairallah. “Most enzymes contain metals. These metals are important for the structural stability or the catalysis of the enzyme. But the majority of simulation packages don’t support metals.”

“We had to do quantum mechanics calculations such as potential energy surface scans, in which we scan for the bonding terms of this metal and see how it’s bonded to the atoms in the active side,” Khairallah continues. “Once we scan it, we derive an optimum bond length and force constant, and then we feed these parameters into the energy function that is part of the simulation package. We use the CHARMM simulation package to simulate the enzyme.”

Of course, simply finding a compound that performs the way the bioinformaticians expect is only the beginning. After discovering a suitable candidate compound, Khairallah must pass it onto biochemists who are then able to test it for best activity as well as toxicity level. Using simulations allows biochemists to only test the most promising compounds.

The great equalizer

Despite a history of bias and discrimination, the scientific community has taken big strides toward inclusivity in recent years. Supporting those efforts is a central goal of Women in HPC (WHPC), an organization working to bring more women into the world of supercomputing. Khairallah is a proud WHPC member, and her story is an example of the equalizing nature of science.

<strong>Making a contribution.</strong> Khairallah presents her work at the ISC19 supercomputing conference in Frankfurt, Germany.  Courtesy Alisa Alering.“I feel like I’m lucky to be in science,” says Khairallah. “Where I grew up (in Sudan), science didn’t get much attention. I developed my own interest because of a close friend from the USA. I was the only one in my family that was curious to see what was beyond my culture or gender limitations. “

Khairallah also spoke of the wonderful community she has found through WHPC. While her membership facilitated the presentation of her work at the ISC supercomputing conference, she hopes that the “rewarding experience” of community she found there will be extended beyond the conference.

In fact, community is what it’s all about for Khairallah. In her eyes, it’s collaboration that makes science worthwhile.

“In science, it’s just a contribution,” says Khairallah. “You have to contribute to the knowledge. It doesn’t matter how big, it’s just that you’re contributing toward it. My contribution gives me a great sense of accomplishment.”

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