Drug-efficacy depends on the inhibitor type and the target position in a metabolic network--a systematic study
Journal of Theoretical Biology, 252 (3):
442--455 (June 2008)PMID: 17981303.DOI: 10.1016/j.jtbi.2007.09.027
Abstract
Drug discovery usually focuses on candidate molecules that affect individual reactions with presumed essential functions in the cellular reaction network, especially in the development of diseases. Unfortunately, appropriately designed drugs often fail to show the expected biological effect, since the multitude of interactions in the biochemical reaction network buffers the individual changes or causes significant side effects. We address this problem through a computational approach, which considers the effect of drug application within a generalized biochemical pathway and by studying the effect of changes regarding the type and strength of inhibitors on the reduction of flux. This allows us to systematically search for the appropriate target and for type and concentration of the optimal inhibitor. We propose the flux selectivity as a measure for the discrimination of the effect on different pathways. Since the calculation of the flux selectivity is based on flux control coefficients that are calculated in the non-affected state, it is also a means for predicting the inhibitor efficacy. Furthermore, we will propose how to increase discriminative inhibition in the case of a parasitic disease by using multi-target drugs. This work is devoted to the memorial of our teacher Reinhart Heinrich, who made important contributions to the investigation of the regulation of metabolic networks, namely by introducing and applying the concept of metabolic control.