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- Title
A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs.
- Authors
Sutherland, Jeffrey J.; Yonchev, Dimitar; Fekete, Alexander; Urban, Laszlo
- Abstract
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 are unique to SPD, with bias towards higher activity in public resources. Annotating drugs with free maximal plasma concentrations, we find 684 physiologically relevant unpublished off-target activities. Furthermore, 64% of putative ADRs linked to target activity in key literature reviews are not statistically significant in SPD. Systematic analysis of all target-ADR pairs identifies several putative associations supported by publications. Finally, candidate mechanisms for known ADRs are proposed based on SPD off-target activities. Here we present a freely-available resource for benchmarking ADR predictions, explaining phenotypic activity and investigating clinical properties of marketed drugs. In vitro secondary pharmacology assays are used to predict the clinical adverse event risks of new drugs. Here, the authors describe a new database, identify the most predictive assays for estimating risk, and propose candidate mechanisms to explain clinically observed risk profiles.
- Subjects
DRUG side effects; PHARMACOLOGY; INVESTIGATIONAL drugs; DATABASES; DRUGS
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40064-9