Network-based assessment of the selectivity of metabolic drug targets in Plasmodium falciparum with respect to human liver metabolism

Using the well-curated metabolic networks PlasmoNet of the parasite Plasmodium falciparum and HepatoNet1 of the human hepatocyte, the selectivity of 48 experimental antimalarial drug targets was analyzed. Applying in silico gene deletions, 24 of these drug targets were found to be perfectly selective, in that they were essential for the parasite but non-essential for the human cell. The selectivity of a subset of enzymes, that were essential in both models, was evaluated with the reduced fitness concept. It was, then, possible to quantify the reduction in functional fitness of the two networks under the progressive inhibition of the same enzymatic activity. Overall, this in silico analysis provided a selectivity ranking that was in line with numerous in vivo and in vitro observations.Genome-scale models can be useful to depict and quantify the effects of enzymatic inhibitions on the impaired production of biomass components. From the perspective of a host-pathogen metabolic interaction, an estimation of the drug targets-induced consequences can be beneficial for the development of a selective anti-parasitic drug.An ideal drug should tackle the disease-causing processes in the most selective way, i.e. with no harm for the healthy cells. To our knowledge, such a perfectly selective drug does not exist. In fact, administrated chemicals can trigger at least secondary consequences (off-target effects) in the organism or in host cells [1]. In case of anti-parasitic drugs, side-effects on the metabolism of host cells may arise from the binding to homologous proteins that share a long evolutionary history with the parasite [2]. To minimize such side-effects, analyses on the performance of multiple networks and the consequences of enzymatic homologous inhibitions may be useful. Ideally, this analysis should be based on detailed mechanistic models of the metabolic networks of the parasite and the host cell pathways [3,4]. However, all the kinetic information needed for the cr