Research grant to help crystallise malaria mystery

Encouraging results are flowing for Australian researchers using computer graphics to find inhibitors of a protein that plays a pivotal role in the life cycle of the parasite that causes malaria.

A research team led by X-ray crystallographer Dr Luke Guddat of the University of Queensland is working with high resolution 3D images of the enzyme which helps synthesise DNA for the malarial parasite, Plasmodium falciparum.

Using specialised software packages, the team is screening libraries of chemical compounds in search of those capable of docking with the salvage enzyme, 6-oxopurine phosphoribosyltransferase.

Such candidates potentially represent effective anti-malarial agents because inhibition of the enzyme could prevent the parasite from making purine nucleotides by purine base salvage.

The team, which recently won a $270,000 NHMRC grant for their project, is also conducting kinetic assays to compare actual binding results with computer predictions.

Guddat is working with high-resolution images of the enzyme whose structure was recently determined for the first time by X-ray crystallographers at the US-based Albert Einstein College of Medicine.

The Queensland researchers have access to databases of the structural coordinates of hundreds of thousands of compounds maintained by the US National Cancer Institute and chemicals companies such as Maybridge.

Using the GOLD docking software package from the Cambridge Crystallographic Data Centre, the team can test as many as 10,000 molecules a day against the enzyme.

Their research program has already turned up some lead candidates with near nanomolar binding affinities, a rating which would spur further interest if it emerged in a drug company discovery program.

As a next step, Guddat will conduct X-ray crystallographic analysis of crystals grown from complexes between the enzyme and putative inhibitors to determine the precise interactions between the test compound and the enzyme.

One reason the team won the NHMRC funding is its exceptionally broad base. The team consists of Guddat, Dr Dianne Keough and Prof John de Jersey who are expert enzymologists as well as Dr Craig Williams, an organic chemist who will design and synthesize second generation inhibitors. Collaboration with Prof Michael Good's team at Queensland Institute of Medical Research is part of the project and this will allow in vivo testing of the compounds.

This implies it has the resources to take a computer-nominated candidate through to a proof-of-concept stage at which investors could potentially be interested in it.

Thanks to research stretching back many years, beginning at Princess Alexandra Hospital, Queensland is one of two locations worldwide with the deepest pool of expertise on the enzyme.

Recently the genome database for the malarial parasite and the anopheles mosquito have been completed so that in future newly discovered proteins will become available to investigate as drug targets by this method.