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Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence
Safety-related drug failures remain a major challenge for the pharmaceutical industry. One approach to ensuring drug safety involves assessing small molecule drug specificity by examining the ability of a drug candidate to interact with a panel of “off-target” proteins, referred to as secondary phar...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358245/ https://www.ncbi.nlm.nih.gov/pubmed/30346593 http://dx.doi.org/10.1093/toxsci/kfy265 |
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author | Deaton, Aimee M Fan, Fan Zhang, Wei Nguyen, Phuong A Ward, Lucas D Nioi, Paul |
author_facet | Deaton, Aimee M Fan, Fan Zhang, Wei Nguyen, Phuong A Ward, Lucas D Nioi, Paul |
author_sort | Deaton, Aimee M |
collection | PubMed |
description | Safety-related drug failures remain a major challenge for the pharmaceutical industry. One approach to ensuring drug safety involves assessing small molecule drug specificity by examining the ability of a drug candidate to interact with a panel of “off-target” proteins, referred to as secondary pharmacology screening. Information from human genetics and pharmacology can be used to select proteins associated with adverse effects for such screening. In an analysis of marketed drugs, we found a clear relationship between the genetic and pharmacological phenotypes of a drug’s off-target proteins and the observed drug side effects. In addition to using this phenotypic information for the selection of secondary pharmacology screens, we also show that it can be used to help identify drug off-target protein interactions responsible for drug-related adverse events. We anticipate that this phenotype-driven approach to secondary pharmacology screening will help to reduce safety-related drug failures due to drug off-target protein interactions. |
format | Online Article Text |
id | pubmed-6358245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63582452019-02-08 Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence Deaton, Aimee M Fan, Fan Zhang, Wei Nguyen, Phuong A Ward, Lucas D Nioi, Paul Toxicol Sci Secondary Pharmacology Screening with Human Evidence Safety-related drug failures remain a major challenge for the pharmaceutical industry. One approach to ensuring drug safety involves assessing small molecule drug specificity by examining the ability of a drug candidate to interact with a panel of “off-target” proteins, referred to as secondary pharmacology screening. Information from human genetics and pharmacology can be used to select proteins associated with adverse effects for such screening. In an analysis of marketed drugs, we found a clear relationship between the genetic and pharmacological phenotypes of a drug’s off-target proteins and the observed drug side effects. In addition to using this phenotypic information for the selection of secondary pharmacology screens, we also show that it can be used to help identify drug off-target protein interactions responsible for drug-related adverse events. We anticipate that this phenotype-driven approach to secondary pharmacology screening will help to reduce safety-related drug failures due to drug off-target protein interactions. Oxford University Press 2019-02 2018-10-22 /pmc/articles/PMC6358245/ /pubmed/30346593 http://dx.doi.org/10.1093/toxsci/kfy265 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contactjournals.permissions@oup.com |
spellingShingle | Secondary Pharmacology Screening with Human Evidence Deaton, Aimee M Fan, Fan Zhang, Wei Nguyen, Phuong A Ward, Lucas D Nioi, Paul Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence |
title | Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence |
title_full | Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence |
title_fullStr | Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence |
title_full_unstemmed | Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence |
title_short | Rationalizing Secondary Pharmacology Screening Using Human Genetic and Pharmacological Evidence |
title_sort | rationalizing secondary pharmacology screening using human genetic and pharmacological evidence |
topic | Secondary Pharmacology Screening with Human Evidence |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358245/ https://www.ncbi.nlm.nih.gov/pubmed/30346593 http://dx.doi.org/10.1093/toxsci/kfy265 |
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