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Determining the Degree of Promiscuity of Extensively Assayed Compounds
In the context of polypharmacology, an emerging concept in drug discovery, promiscuity is rationalized as the ability of compounds to specifically interact with multiple targets. Promiscuity of drugs and bioactive compounds has thus far been analyzed computationally on the basis of activity annotati...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833426/ https://www.ncbi.nlm.nih.gov/pubmed/27082988 http://dx.doi.org/10.1371/journal.pone.0153873 |
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author | Jasial, Swarit Hu, Ye Bajorath, Jürgen |
author_facet | Jasial, Swarit Hu, Ye Bajorath, Jürgen |
author_sort | Jasial, Swarit |
collection | PubMed |
description | In the context of polypharmacology, an emerging concept in drug discovery, promiscuity is rationalized as the ability of compounds to specifically interact with multiple targets. Promiscuity of drugs and bioactive compounds has thus far been analyzed computationally on the basis of activity annotations, without taking assay frequencies or inactivity records into account. Most recent estimates have indicated that bioactive compounds interact on average with only one to two targets, whereas drugs interact with six or more. In this study, we have further extended promiscuity analysis by identifying the most extensively assayed public domain compounds and systematically determining their promiscuity. These compounds were tested in hundreds of assays against hundreds of targets. In our analysis, assay promiscuity was distinguished from target promiscuity and separately analyzed for primary and confirmatory assays. Differences between the degree of assay and target promiscuity were surprisingly small and average and median degrees of target promiscuity of 2.6 to 3.4 and 2.0 were determined, respectively. Thus, target promiscuity remained at a low level even for most extensively tested active compounds. These findings provide further evidence that bioactive compounds are less promiscuous than drugs and have implications for pharmaceutical research. In addition to a possible explanation that drugs are more extensively tested for additional targets, the results would also support a “promiscuity enrichment model” according to which promiscuous compounds might be preferentially selected for therapeutic efficacy during clinical evaluation to ultimately become drugs. |
format | Online Article Text |
id | pubmed-4833426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-48334262016-04-22 Determining the Degree of Promiscuity of Extensively Assayed Compounds Jasial, Swarit Hu, Ye Bajorath, Jürgen PLoS One Research Article In the context of polypharmacology, an emerging concept in drug discovery, promiscuity is rationalized as the ability of compounds to specifically interact with multiple targets. Promiscuity of drugs and bioactive compounds has thus far been analyzed computationally on the basis of activity annotations, without taking assay frequencies or inactivity records into account. Most recent estimates have indicated that bioactive compounds interact on average with only one to two targets, whereas drugs interact with six or more. In this study, we have further extended promiscuity analysis by identifying the most extensively assayed public domain compounds and systematically determining their promiscuity. These compounds were tested in hundreds of assays against hundreds of targets. In our analysis, assay promiscuity was distinguished from target promiscuity and separately analyzed for primary and confirmatory assays. Differences between the degree of assay and target promiscuity were surprisingly small and average and median degrees of target promiscuity of 2.6 to 3.4 and 2.0 were determined, respectively. Thus, target promiscuity remained at a low level even for most extensively tested active compounds. These findings provide further evidence that bioactive compounds are less promiscuous than drugs and have implications for pharmaceutical research. In addition to a possible explanation that drugs are more extensively tested for additional targets, the results would also support a “promiscuity enrichment model” according to which promiscuous compounds might be preferentially selected for therapeutic efficacy during clinical evaluation to ultimately become drugs. Public Library of Science 2016-04-15 /pmc/articles/PMC4833426/ /pubmed/27082988 http://dx.doi.org/10.1371/journal.pone.0153873 Text en © 2016 Jasial et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Jasial, Swarit Hu, Ye Bajorath, Jürgen Determining the Degree of Promiscuity of Extensively Assayed Compounds |
title | Determining the Degree of Promiscuity of Extensively Assayed Compounds |
title_full | Determining the Degree of Promiscuity of Extensively Assayed Compounds |
title_fullStr | Determining the Degree of Promiscuity of Extensively Assayed Compounds |
title_full_unstemmed | Determining the Degree of Promiscuity of Extensively Assayed Compounds |
title_short | Determining the Degree of Promiscuity of Extensively Assayed Compounds |
title_sort | determining the degree of promiscuity of extensively assayed compounds |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833426/ https://www.ncbi.nlm.nih.gov/pubmed/27082988 http://dx.doi.org/10.1371/journal.pone.0153873 |
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