Adverse drug reactions (ADRs) are undesirable effects associated with a clinical use of drugs originating from their pharmacological on- and off-target actions. ADRs often prevent patients from receiving life-saving therapies and can severely impair a patient's quality of life. Neuropathy occurs to approximately 15% of all FDA-approved drugs in variable degrees. Despite this high prevalence, there are no published studies identifying the common biological signatures of these neuropathy-causing drugs. The purpose of this study was to develop a comprehensive pharmacological network of drugs, known drug-targets, metabolizing enzymes or transporters, and potential mediators, all of which are associated with neuropathy. Multiple existing and novel bio- and chem-informatics tools were employed to efficiently collect relevant chemical and pharmacological information from multiple knowledge-bases. A text-mining approach was used to identify neuropathy-causing drugs from FDA drug labels (Drugs@FDA and DailyMed) and ADR reports (SIDER). SciMiner, a literature-mining tool, was used to survey all relevant PubMed abstracts and available medical and pharmacology reviews in Drugs@FDA. This approach allowed for identification of clinical information such as severity and frequency of neuropathy for each drug. PubChemSR was used to search and retrieve relevant chemical information from PubChem and ChemSpider. Drug-targets and metabolizing enzymes and transporters of each neuropathy-causing drug, constituting the backbone of the pharmacological network, were collected from multiple databases, including DrugBank, Therapeutic Target Database (TTD), and PharmGKB. Additionally, protein and genomic interaction data collected from BioGRID and neuropathy-related genes from OMIM were incorporated to extend the network. A preliminary analysis of this comprehensive network suggests that neuron projection-associated genes are significantly affected by these drugs, although they are not direct targets. In conclusion, integration of multiple bio- and chem-informatics approaches enabled construction of a comprehensive pharmacological network of drugs commonly causing neuropathy and identified novel pathways that may underlie the pathogenesis of the drug-induced neuropathy.

Informatics tools for interacting with literature and chemical databases to build pharmacological networks of drug-induced neuropathy

246th National Meeting (2013)

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