Abstract
Currently, drug discovery approaches commonly assume a monotonic dose-response relationship. However, the assumption of monotonicity is increasingly being challenged. Here we show that for two simple interacting linear signaling pathways that carry two different signals with different physiological responses, a non-monotonic input-output relation can arise with simple network topologies including coherent and incoherent feed-forward loops. We show that non-monotonicity of the response functions has severe implications for pharmacological treatment. Fundamental constraints are imposed on the effectiveness and toxicity of any drug independent of its chemical nature and selectivity due to the specific network structure.
Highlights
A key question is whether network dynamics and topology reveal constraints on the form of the pharmacological response and provide insights into toxicity and effectiveness[11,12,13,14]
We study the implications of non-monotonicity for pharmacodynamics of two example topologies
We note that network topologies that contain coherent and incoherent feed-forward loops, do not necessarily show non-monotonicity
Summary
Not every topology with an incoherent feed-forward loop shows non-monotonicity. This does not imply that non-monotonic behavior for these topologies is impossible. We first select one 6 node network that has a single incoherent feed-forward loop (Fig. 1b.3); the activating connections S1 − V, S2 − W, V − X1 and X1 − X2, while V and W both repress X2 This network, for specific parameters, displays a non-monotonic relation between S1 and X2. A further increase of agonist would eventually remove the toxicity, while remaining effective (see Fig. 5b, starting from ) This is a direct consequence of the non-monotonic relation between S1 and X2. The direction of driving in this example determines the toxicity of the drug, but does not change the effectiveness This is an immediate consequence of the non-monotonic relation between V and X2, combined with the initial position of the system. C) Similar to b), but with the roles of S1 and S2 reversed
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