The Biochemical Basis of Hormesis
Cerrillo, G.; vidakovic, H.; Miguez, d. G.
Show 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Epigenetic Instability May Alter Cell State Transitions and Anticancer Drug Resistance 96%
- Bivalent chromatin as a therapeutic target in cancer: An in silico predictive approach for combining epigenetic drugs 96%
- Elucidating multi-input processing 3-node gene regulatory network topologies capable of generating striped gene expression patterns 95%
Similar papers in this journal
- Degeneracy measures in biologically plausible random Boolean networks 95%
- TopoDoE: A Design of Experiment strategy for selection and refinement in ensembles of executable Gene Regulatory Networks 95%
- Exact calculation of stationary solution and parameter sensitivity analysis of stochastic continuous time Boolean models 95%
Similar papers in this journal
- Computational quantification of global effects induced by mutations and drugs in signaling networks of colorectal cancer cells. 96%
- BAX and SMAC Regulate Bistable Properties of the Apoptotic Caspase System 95%
- aiMeRA: A generic modular response analysis R package and its application to estrogen and retinoic acid receptors crosstalk 95%
Similar papers in this journal
- Protein-protein complexes can undermine ultrasensitivity-dependent biological adaptation 96%
- Multistability in cellular differentiation enabled by a network of three mutually repressing master regulators 95%
- Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression 95%
Similar papers in this journal
- Integration of transcriptomics data into agent-based models of solid tumor metastasis 94%
- Immune and non-immune cell fencing of tumor cells is a widespread and functionally relevant spatial pattern in solid cancers 93%
- Digital Cousins: Simultaneous Optimization of One Model for BMP Signaling in Distant Relatives Reveals Essential Core 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.