Drug Safety

, Volume 41, Issue 11, pp 1059–1072 | Cite as

Predicting Adverse Drug Effects from Literature- and Database-Mined Assertions

  • Mary K. La
  • Alexander Sedykh
  • Denis Fourches
  • Eugene Muratov
  • Alexander TropshaEmail author
Original Research Article



Given that adverse drug effects (ADEs) have led to post-market patient harm and subsequent drug withdrawal, failure of candidate agents in the drug development process, and other negative outcomes, it is essential to attempt to forecast ADEs and other relevant drug–target–effect relationships as early as possible. Current pharmacologic data sources, providing multiple complementary perspectives on the drug–target–effect paradigm, can be integrated to facilitate the inference of relationships between these entities.


This study aims to identify both existing and unknown relationships between chemicals (C), protein targets (T), and ADEs (E) based on evidence in the literature.

Materials and Methods

Cheminformatics and data mining approaches were employed to integrate and analyze publicly available clinical pharmacology data and literature assertions interrelating drugs, targets, and ADEs. Based on these assertions, a C–T–E relationship knowledge base was developed. Known pairwise relationships between chemicals, targets, and ADEs were collected from several pharmacological and biomedical data sources. These relationships were curated and integrated according to Swanson’s paradigm to form C–T–E triangles. Missing C–E edges were then inferred as C–E relationships.


Unreported associations between drugs, targets, and ADEs were inferred, and inferences were prioritized as testable hypotheses. Several C–E inferences, including testosterone → myocardial infarction, were identified using inferences based on the literature sources published prior to confirmatory case reports. Timestamping approaches confirmed the predictive ability of this inference strategy on a larger scale.


The presented workflow, based on free-access databases and an association-based inference scheme, provided novel C–E relationships that have been validated post hoc in case reports. With refinement of prioritization schemes for the generated C–E inferences, this workflow may provide an effective computational method for the early detection of potential drug candidate ADEs that can be followed by targeted experimental investigations.



The authors would like to thank Mr Alexander Gartland for fruitful discussions that helped to improve the quality of the manuscript.

The MedDRA® trademark is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on behalf of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

Compliance with Ethical Standards


This study was supported in part by the National Institutes of Health (Grant 1U01CA207160).

Conflict of interest

Mary La, Alexander Sedykh, Denis Fourches, Eugene Muratov, and Alexander Tropsha declare no conflict of interests that are directly relevant to the content of this study.

Supplementary material

40264_2018_688_MOESM1_ESM.pdf (601 kb)
Supplementary material 1 (PDF 601 kb)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Practice Advancement and Clinical EducationUNC Eshelman School of PharmacyChapel HillUSA
  2. 2.Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal ChemistryUNC Eshelman School of PharmacyChapel HillUSA
  3. 3.Sciome LLCResearch Triangle ParkUSA
  4. 4.Department of ChemistryNorth Carolina State UniversityRaleighUSA

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