Integration and mining of malaria molecular, functional and pharmacological data: how far are we from a chemogenomic knowledge space?

Abstract

The organization and mining of malaria genomic and post-genomic data is important to significantly increase the knowledge of the biology of its causative agents, and is motivated, on a longer term, by the necessity to predict and characterize new biological targets and new drugs. Biological targets are sought in a biological space designed from the genomic data from Plasmodium falciparum, but using also the millions of genomic data from other species. Drug candidates are sought in a chemical space containing the millions of small molecules stored in public and private chemolibraries. Data management should, therefore, be as reliable and versatile as possible. In this context, five aspects of the organization and mining of malaria genomic and post-genomic data were examined: 1) the comparison of protein sequences including compositionally atypical malaria sequences, 2) the high throughput reconstruction of molecular phylogenies, 3) the representation of biological processes, particularly metabolic pathways, 4) the versatile methods to integrate genomic data, biological representations and functional profiling obtained from Xomic experiments after drug treatments and 5) the determination and prediction of protein structures and their molecular docking with drug candidate structures. Recent progress towards a grid-enabled chemogenomic knowledge space is discussed.

Plasmodium falciparum Apicoplast Drugs: Targets or Off-Targets?

“…falciparum proteins of prokaryotic origin might be designed based on differences between bacterial and malarial proteins. In particular, large amino acid insertions (often predicted to be disordered stretches) are often detected in the sequences of malaria proteins. − Molecular modeling of Plasmodium DNA gyrase B has thus revealed extensive fold conservation with Escherichia coli counterpart but also large disordered insertions in close proximity to the sites of action . Future progress might benefit of the presence of such domains to design antibiotic analogues binding specifically to P.…”

Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery

“…In the past few years, there have been strong demands to generate and integrate molecular, functional and pharmacological data into a common malaria-related chemogenomic knowledge space [5]. Several initiatives have contributed greatly to promote such community efforts to facilitate the discovery of a next generation of malaria drugs.…”