The Biochemical Basis of Hormesis

Abstract Atypical dose-response curves, where the effect of a drug does not follow a monotonic shape, are unsuitable but common in drug development. Here, we develop a high-throughput computational screening to search for features that could induce this type of complex hormetic relation between changes in drug concentration and changes in drug effect. Our study suggests that all hormetic networks share a similar core structure: an incoherent bivalent network motif centered on the target of the drug. In addition, the probability of producing a biphasic dose response requires that one of the interactions operating in the saturated regime. This insight is applied to explain how hormesis exhibited during long-term rapamycin treatment arises directly from the structure of the network of interactions that form the mTOR-Pi3K-Akt signaling pathway. Overall, our study shows that drug hormesis can be explained and predicted, and should not be a cause for automatic rejection in the drug development pipeline.