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Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

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Context-specific organ metabolic modeling.

Preliminary constraints were imposed upon metabolite exchange fluxes of the full metabolic network based on coordinated experimental detection of transportable metabolites both in the organ tissue and the biofluids processed by the organ. Metabolites detected in both biofluid and organ were assumed freely exchangeable in the model, and the remainder of the metabolite exchanges were tentatively constrained to zero. Organ physiology literature was reviewed to compile an objective function consisting of the metabolic functions of the organ. Each function was tested for compatibility with the preliminary model. Metabolite exchange, transport, and demand reactions required to achieve some functions were added to the network, and exchange fluxes for objective metabolites were directionally constrained in accordance with the literature. Functions not compatible with the model were removed from the overall objective function. The objective function was then integrated with gene expression data obtained from an organ tissue sample to derive a net, context-specific metabolic organ model representing the metabolic exchange between the organ and the rest of the body and the metabolic reactions that take place within the organ to achieve this exchange.

Figure 1

doi: https://doi.org/10.1371/journal.pcbi.1000938.g001