David Fell
Oxford Brookes University
dfell@brookes.ac.uk
The IC50 for the response of a cell system to an inhibitory drug, even after correction for its actual concentration at its site of action, always tends to be much greater than the drug’s Ki for its target. In the case of drugs directed against metabolism, the reasons for this arise in the general properties of metabolic systems and can be understood in terms of metabolic control analysis, which provides both theoretical reasons and experimental illustrations. Metabolic control analysis also suggests that the discrepancy between the IC50 and the Ki will be different for different targets in the same pathway, to an extent that is largely determined by the systemic properties of the pathway, and only to a limited degree by the properties of the drug. Competitive inhibitors will, however, generally perform worse than uncompetitive inhibitors or inactivators. These aspects of the systemic response to an inhibitor can be explored by computer simulation even before a suitable drug candidate has been discovered.
Although metabolic control analysis does not apply directly to signal transduction pathways, computer simulation studies reveal that similar principles are likely to be relevant. Indeed, modelling a growth factor signalling pathway shows that the so-called paradoxical effects of a candidate drug are a predictable response of the system.
However, modelling the response of a single pathway to a static drug concentration is only a beginning. The full potential of the approach will come first from being able to simulate the response to a time-varying drug concentration corresponding to a particular therapeutic regimen, and secondly from simulating the overall response of a heterogeneous population of cells.