Cargando…
Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects
BACKGROUND: Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects....
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408384/ https://www.ncbi.nlm.nih.gov/pubmed/28449705 http://dx.doi.org/10.1186/s40360-017-0128-7 |
_version_ | 1783232294450888704 |
---|---|
author | Chartier, Matthieu Morency, Louis-Philippe Zylber, María Inés Najmanovich, Rafael J. |
author_facet | Chartier, Matthieu Morency, Louis-Philippe Zylber, María Inés Najmanovich, Rafael J. |
author_sort | Chartier, Matthieu |
collection | PubMed |
description | BACKGROUND: Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects. METHODS: We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects. RESULTS: We observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases. CONCLUSIONS: The detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40360-017-0128-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5408384 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-54083842017-05-02 Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects Chartier, Matthieu Morency, Louis-Philippe Zylber, María Inés Najmanovich, Rafael J. BMC Pharmacol Toxicol Research Article BACKGROUND: Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects. METHODS: We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects. RESULTS: We observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases. CONCLUSIONS: The detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40360-017-0128-7) contains supplementary material, which is available to authorized users. BioMed Central 2017-04-28 /pmc/articles/PMC5408384/ /pubmed/28449705 http://dx.doi.org/10.1186/s40360-017-0128-7 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Chartier, Matthieu Morency, Louis-Philippe Zylber, María Inés Najmanovich, Rafael J. Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects |
title | Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects |
title_full | Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects |
title_fullStr | Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects |
title_full_unstemmed | Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects |
title_short | Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects |
title_sort | large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408384/ https://www.ncbi.nlm.nih.gov/pubmed/28449705 http://dx.doi.org/10.1186/s40360-017-0128-7 |
work_keys_str_mv | AT chartiermatthieu largescaledetectionofdrugofftargetshypothesesfordrugrepurposingandunderstandingsideeffects AT morencylouisphilippe largescaledetectionofdrugofftargetshypothesesfordrugrepurposingandunderstandingsideeffects AT zylbermariaines largescaledetectionofdrugofftargetshypothesesfordrugrepurposingandunderstandingsideeffects AT najmanovichrafaelj largescaledetectionofdrugofftargetshypothesesfordrugrepurposingandunderstandingsideeffects |