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Network-Based Selectivity of Antiparasitic Inhibitors


Klipp,  Edda
Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Bakker, B. M., Assmus, H. E., Bruggeman, F., Haanstra, J. R., Klipp, E., & Westerhoff, H. (2002). Network-Based Selectivity of Antiparasitic Inhibitors. Molecular Biology Reports, 29(1 - 2), 1-5.

Several diseases are caused by eukaryotic parasites, e.g. Malaria or African Sleeping Disease. One possible way to proceed against them is the knockout or an adequate inhibition of the parasite's metabolism by capable drugs, i.e. by inhibitors with a strong effect on the parasitic metabolism and a least possible effect in the host. The development of such drugs is complicated by the substantial problem of the biochemical similarity between the metabolisms of hosts and parasites. Especially in their essential parts, which are the most suited targets for the knockout, both metabolic systems are closely related. Therefore drug research in that field focuses on selectivity, i.e. capacity of an inhibiting drug to differentiate between host and parasite. Structure-based selectivity, which deals with differences in inhibitor binding as a result of the 3D-structure of the inhibited enzymes, dominates the interest of research, whereas network-based selectivity, which comprehends the properties of a metabolic network as they are described in Metabolic Control Theory, is almost neglected. The study of network-based selectivity should lead to a prediction of promising target enzymes for drugs as well as of the best suited inhibiting mechanism, e.g. competitive, non-competitive or uncompetitive inhibition.By the means of a newly defined term we have compared the selectivity of these different types of inhibitors for the first and the second step of a two-enzyme pathway. We also tried to generalize our findings for a linear pathway of arbitrary length. The method of comparing the flux control distribution or 'control profile' in a metabolic system of the parasite and the host for prediction of most effective targets for anti-parasitic drugs is called Differential Control Analysis (Bakker et al. 2000). The models of the glycolysis of the human erythrocyte (Schuster & Holzhütter 1995) and of Trypanosoma brucei (Bakker et al. 1997) are looked into in more detail.