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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...

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Autores principales: Deaton, Aimee M, Fan, Fan, Zhang, Wei, Nguyen, Phuong A, Ward, Lucas D, Nioi, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
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.
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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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