Drug target prediction using adverse event report systems: a pharmacogenomic approach

Abstract

Motivation: Unexpected drug activities derived from off-targets are usually undesired and harmful; however, they can occasionally be beneficial for different therapeutic indications. There are many uncharacterized drugs whose target proteins (including the primary target and off-targets) remain unknown. The identification of all potential drug targets has become an important issue in drug repositioning to reuse known drugs for new therapeutic indications.

Results: We defined pharmacological similarity for all possible drugs using the US Food and Drug Administration's (FDA's) adverse event reporting system (AERS) and developed a new method to predict unknown drug-target interactions on a large scale from the integration of pharmacological similarity of drugs and genomic sequence similarity of target proteins in the framework of a pharmacogenomic approach. The proposed method was applicable to a large number of drugs and it was useful especially for predicting unknown drug-target interactions that could not be expected from drug chemical structures. We made a comprehensive prediction for potential off-targets of 1874 drugs with known targets and potential target profiles of 2519 drugs without known targets, which suggests many potential drug-target interactions that were not predicted by previous chemogenomic or pharmacogenomic approaches.

Availability: Softwares are available upon request.

Contact: yamanishi@bioreg.kyushu-u.ac.jp

Supplementary information: Datasets and all results are available at http://cbio.ensmp.fr/~yyamanishi/aers/.

Fig. 1.

Venn diagram of all possible drugs (left) and drugs with target information (right) across AERS, SIDER and JAPIC.

Fig. 2.

Part of drug–target interaction network obtained from AERS-freq in this study. Circles and rectangles indicate drugs and target proteins, respectively, where the drugs are represented by the KEGG DRUG IDs. Black bold lines indicate known drug–target interactions. Gray solid lines and dotted lines indicate predicted (score ≥ 100) drug–target interactions and the similar drug pairs, respectively. Drugs with similar efficacy were located as close as possible and shadowed where possible