Computer-assisted drug design for Malaria

Researchers at the Uppsala University (Sweden) are using a computer-assisted strategy for rapid drug design for various diseases. This week they published very encouraging results where they describe the exclusive use of bioinformatics software to develop new potential drug candidates against a newly discovered, essential enzyme of the Malaria-inducing parasite, Plasmodium falciparum.

They essentially used BLAST-like algorithms to find enzymes sharing significant similarities with it, found X-rays determined 3D structures associated with the similar enzymes and "aligned" the amino acids sequence of Plasmodium falciparum enzyme to the known structures (EsyPred 3D is an example of a bioinformatics package able to do this, although they might have developed their own). Then, they used bioinformatics software able to calculate free-energy and docking affinity of compounds (a small peptide in their case) to the active site. Their approach is unique because they didn't experimentally determined the structure of their enzyme. However, it has serious limitations; you have to be able to find significant homology with known structures, and even then, prediction of structure for amino acids who are not fitting the model is lousy at best. Still, for a well known family of enzymes with a well-determined active site, its full of potential. Website of the group

Press release (thanks Innovation-reports.de) :

New malaria enzyme laid bare with help of computer calculationsUsing
only computers, a research team at Uppsala University in Sweden has
managed to reveal both the structure and the function of a newly
discovered enzyme from the most dangerous malaria parasite, Plasmodium
falciparum. All that was needed was the amino acid sequence of the
enzyme. The findings may represent a breakthrough for future
pharmaceutical research.
The research was carried out within the framework of a project (RAPID)
at the Uppsala University Center for Structural Biology, Medical
Chemistry, and Computer Chemistry, which was established last year and
is directed by Professor Alwyn Jones. The aim is to develop drugs for
some of the most severe and widely spread diseases in the world, such
as malaria and TB. The results, which recently came out as an
“accelerated publication” in the journal Biochemistry, are the work of
Professor Johan Åqvist and doctoral student Sinisa Bjelic.
“The enzyme we studied is a new type, with previously unknown catalyst
groups. This made it especially interesting as a target molecule for
new drugs. Using only computer calculations, we succeeded in revealing
both what it looks like and how it functions. It’s the first time
anybody ever did that,” says Johan Åqvist.
They started by comparing the enzyme’s amino acid sequence with other
known sequences. Then they ran computer simulations of how it might
move in order to find possible structures, after which they looked at
plausible combinations for how a substrate, a small peptide, might
stick to the enzyme. In this way it was possible to predict the
structure of the enzyme, how the substrate bonds, and the mechanism and
rapidity of the chemical reaction. The fit with experimental data was
good.
“In the past researchers have managed to predict reaction mechanisms on
the basis of known structures, but this time we started from scratch.”
The malaria parasite under study, Plasmodium falciparum, has several
enzymes that directly attack hemoglobin in the blood when it invades.
There is a tremendous interest in these enzymes among drug researchers.
Today 1-3 million people die of malaria every year, and there is
growing concern that the numbers will increase further.
“Millions of people are infected, and the parasite quickly develops
resistance to new drugs,” says Johan Åqvist.