Adverse drug reactions are a substantial cause of early termination of clinical trials and drug withdrawal from the market. Adverse drug reactions are a product of unintended consequences during drug metabolism : drug molecules can be metabolized into reactive metabolites, which can conjugate to biomolecules, like protein and DNA, in a process termed bioactivation. Experimental assays for assessing the formation of reactive metabolites are low-throughput and require investment of substantial resources. In contrast, computational methods are appealing for rapid, high-throughput screening of potentially toxic compounds during the early stages of the drug development pipeline. Commonly used methods focus on detecting and structurally characterizing reactive metabolite-biomolecule adducts or predicting sites on a drug compound that are liable to form reactive metabolites. However, such methods are often only concerned with the structure of the initial drug compound or of the adduct formed when a biomolecule conjugates to a reactive metabolite. Thus, these methods are likely to miss intermediate metabolites that may be required for subsequent reactive metabolite formation. In fact, approximately 57% of drugs that form reactive metabolites require the formation of at least one intermediate metabolite. Therefore, modeling the sequential metabolism of drugs to determine the intermediate metabolite structures that precede reactive metabolite formation would provide a better mechanistic understanding of how reactive metabolites form. We set out to create a tool that can take a compound and a corresponding reactive metabolite and (1) enumerate pathways, or sequences of intermediate metabolite structures, between the pair, and (2) compute the likelihood of those pathways and each individual step preceding reactive metabolite formation. This tool will be applied to withdrawn drugs with known reactive metabolites to identify previously unknown intermediates. Identification of the presence and likelihood of intermediate metabolites in pathways which lead to reactive metabolites could guide rational drug modification in order to lower the likelihood of the intermediate metabolite's formation, which would diminish the chance of reactive metabolite formation.

Modeling drug metabolism identifies intermediate metabolites which precede reactive metabolite formation

2019 Fall National Meeting

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