A Preclinical Secondary Pharmacology Resource Illuminates Target-Adverse Drug Reaction Associations of Marketed Drugs

In vitro secondary pharmacology assays are an important tool for predicting clinical adverse drug reactions (ADRs) of investigational drugs. We created the Secondary Pharmacology Database (SPD) by testing 1958 drugs using 200 assays to validate target-ADR associations. Compared to public and subscription resources, 95% of all and 36% of active (AC50 < 1 µM) results were unique to SPD, with bias towards higher activity in public resources. Annotating drugs with free maximal plasma concentrations, we found 684 physiologically relevant novel off-target activities. Furthermore, 64% of putative ADRs linked to target activity in key literature reviews were not statistically significant in SPD. Systematic analysis of all target-ADR pairs identified several novel associations confirmed by publications. Finally, candidate mechanisms for known ADRs are proposed based on SPD off-target activities. Taken together, we present a unique freely-available resource for benchmarking ADR predictions, explaining novel phenotypic activity and investigating clinical properties of marketed drugs.