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 subscri...

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Autores principales: Sutherland, Jeffrey J., Yonchev, Dimitar, Fekete, Alexander, Urban, Laszlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356841/
https://www.ncbi.nlm.nih.gov/pubmed/37468498
http://dx.doi.org/10.1038/s41467-023-40064-9
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author Sutherland, Jeffrey J.
Yonchev, Dimitar
Fekete, Alexander
Urban, Laszlo
author_facet Sutherland, Jeffrey J.
Yonchev, Dimitar
Fekete, Alexander
Urban, Laszlo
author_sort Sutherland, Jeffrey J.
collection PubMed
description 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 Annotating drugs with free maximal plasma concentrations, we find 684 physiologically relevant unpublished off-target activities.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.
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spelling pubmed-103568412023-07-21 A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs Sutherland, Jeffrey J. Yonchev, Dimitar Fekete, Alexander Urban, Laszlo Nat Commun Article 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. Nature Publishing Group UK 2023-07-19 /pmc/articles/PMC10356841/ /pubmed/37468498 http://dx.doi.org/10.1038/s41467-023-40064-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sutherland, Jeffrey J.
Yonchev, Dimitar
Fekete, Alexander
Urban, Laszlo
A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
title A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
title_full A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
title_fullStr A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
title_full_unstemmed A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
title_short A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
title_sort preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356841/
https://www.ncbi.nlm.nih.gov/pubmed/37468498
http://dx.doi.org/10.1038/s41467-023-40064-9
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