Computational Analysis of Biochemical Networks: Detecting Novel Drug Targets

Biomedical research could enable treating the disease by effectively and specifically targeting essential enzymes of this parasite. However, the parasite has developed resistance to existing drugs making it absolutely necessary to discover new drugs. We have established a simple computational tool which analyses the topology of the metabolic network of Plasmodium falciparum to identify essential enzymes as possible drug targets. We investigated the essentiality of a reaction in the metabolic network by deleting (knocking-out) such a reaction in silico and noted the neighbouring compounds of the investigated reaction that had to be produced by alternative biochemical pathways. Using breadth first searches, we tested qualitatively if these products could be generated by reactions that serve as potential deviations of the metabolic flux. With this we identified 70 essential reactions. Our results were compared with a comprehensive list of 38 targets of approved malaria drugs. When combining our approach with an in silico choke-point analysis, we could improve the precision of the prediction results. Finally we present a refined list of new potential candidate targets.