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iSGTW Feature - WISDOM unplugged: Malaria drug-leads graduate to the wet lab


Feature - WISDOM unplugged: malaria drug-leads graduate to the wet lab

The WISDOM project screened one million molecules for their potential to bind to and inhibit “plasmepsin,” a protein essential for survival of the malaria parasite. The parasite can be transferred to a human host via the mosquito vector.
Image courtesy of PD-USGOV

Hot on the heels of their initial success, WISDOM collaborators have high hopes as their anti-malaria drug-leads move from computer processers to petri dishes.

“We’re excited to be at this stage,” says Ana Lucia Da Costa, WISDOM researcher at CNRS, France. “I can’t wait till we get the next set of results back.”

The WISDOM project, a collaboration of eight core institutions in five countries, began searching for anti-malaria drugs in 2005. Rather than go straight to the lab, the team used a grid-powered software program to screen for potential drug-leads, searching for small molecules—called ligands—that could bind to and disable the malaria protein plasmepsin.

“Disabling this protein essentially starves the parasites to death,” says Da Costa.

Plasmepsin, Da Costa explains, is malaria’s workhorse. Used by the parasite to attack red blood cells in the human body, it can be disarmed using the perfect weapon: a matching ligand; the lock for malaria’s destructive key.

Every year, malaria affects more than 500 million of the world’s poorest people, killing around three million people a year. A child dies from malaria every 30 seconds; an African child has on average between 1.6 and 5.4 episodes of malaria fever each year.
Image courtesy of hdptcar

One in a million

The search for this perfectly matched ligand led the WISDOM team to perform 41 million “dockings,” screening a million molecules and then discarding all but the 30 most promising molecules. This select handful then moved off-screen: undergoing in vitro evaluation in a wet lab at Chonnam National University in South Korea. In a fantastic result, all 30 computer-selected ligands were able to inhibit plasmepsin in the lab, even at nanomolar concentrations.

“This was a great success,” says Da Costa, who helped analyze the results. “We didn’t expect all of the ligands to be active. It shows that our approach worked really well.”

Now these 30 ligands have advanced to the next stage: in vivo testing in living cultures of the malaria parasite at the Commissariat Energie Atomique in France. The testing is ongoing, but initial results show at least one ligand inhibits the parasite life cycle at micromolar concentrations.

The next step will be to test for toxicity to animal cells. If the ligands are safe, the collaboration can begin to pursue new drug approval.

Classical pharmaceutical research often requires 15 years for a drug to be developed and approved. Thanks to grid-power, the WISDOM team have fast-forwarded this scenario and are already in the lab after just three years of research. They are using the same approach to expand into diabetes and avian flu research.

WISDOM uses several grid infrastructures including Enabling Grids for E-sciencE.

- Danielle Venton, EGEE

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