Cargando…
Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine
In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462473/ https://www.ncbi.nlm.nih.gov/pubmed/28542202 http://dx.doi.org/10.1371/journal.pntd.0005629 |
_version_ | 1783242519287431168 |
---|---|
author | Tegazzini, Diana Cantizani, Juan Peña, Imanol Martín, Julio Coterón, Jose M. |
author_facet | Tegazzini, Diana Cantizani, Juan Peña, Imanol Martín, Julio Coterón, Jose M. |
author_sort | Tegazzini, Diana |
collection | PubMed |
description | In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the “Leishmania donovani box” were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed. The potency of each compound was determined every 24 hours up to 96 hours, and standard drugs amphotericin B and miltefosine were used as references to group these compounds according to their rate of action. Independently of this biological assessment, compounds were also clustered according to their minimal chemical scaffold. Comparison of the results showed a complete correlation between the chemical scaffold and the biological group for the vast majority of compounds, demonstrating how the assay was able to bring information on the rate of action for each chemical series, a property directly linked to the mode of action. Overall, the assay here described permitted us to evaluate the rate of action of the “Leishmania donovani box” using two of the currently available drugs as references and, also, to propose a number of fast-acting chemical scaffolds present in the box as starting points for future drug discovery projects to the wider scientific community. The results here presented validate the use of this assay for the determination of the rate of action early in the discovery process, to assist in the prioritisation of hit compounds. |
format | Online Article Text |
id | pubmed-5462473 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54624732017-06-26 Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine Tegazzini, Diana Cantizani, Juan Peña, Imanol Martín, Julio Coterón, Jose M. PLoS Negl Trop Dis Research Article In recent years, the neglected diseases drug discovery community has elected phenotypic screening as the key approach for the identification of novel hit compounds. However, when this approach is applied, important questions related to the mode of action for these compounds remain unanswered. One of such questions is related to the rate of action, a useful piece of information when facing the challenge of prioritising the most promising hit compounds. In the present work, compounds of the “Leishmania donovani box” were evaluated using a rate of action assay adapted from a replicative intracellular high content assay recently developed. The potency of each compound was determined every 24 hours up to 96 hours, and standard drugs amphotericin B and miltefosine were used as references to group these compounds according to their rate of action. Independently of this biological assessment, compounds were also clustered according to their minimal chemical scaffold. Comparison of the results showed a complete correlation between the chemical scaffold and the biological group for the vast majority of compounds, demonstrating how the assay was able to bring information on the rate of action for each chemical series, a property directly linked to the mode of action. Overall, the assay here described permitted us to evaluate the rate of action of the “Leishmania donovani box” using two of the currently available drugs as references and, also, to propose a number of fast-acting chemical scaffolds present in the box as starting points for future drug discovery projects to the wider scientific community. The results here presented validate the use of this assay for the determination of the rate of action early in the discovery process, to assist in the prioritisation of hit compounds. Public Library of Science 2017-05-25 /pmc/articles/PMC5462473/ /pubmed/28542202 http://dx.doi.org/10.1371/journal.pntd.0005629 Text en © 2017 Tegazzini 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 Tegazzini, Diana Cantizani, Juan Peña, Imanol Martín, Julio Coterón, Jose M. Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine |
title | Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine |
title_full | Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine |
title_fullStr | Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine |
title_full_unstemmed | Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine |
title_short | Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine |
title_sort | unravelling the rate of action of hits in the leishmania donovani box using standard drugs amphotericin b and miltefosine |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462473/ https://www.ncbi.nlm.nih.gov/pubmed/28542202 http://dx.doi.org/10.1371/journal.pntd.0005629 |
work_keys_str_mv | AT tegazzinidiana unravellingtherateofactionofhitsintheleishmaniadonovaniboxusingstandarddrugsamphotericinbandmiltefosine AT cantizanijuan unravellingtherateofactionofhitsintheleishmaniadonovaniboxusingstandarddrugsamphotericinbandmiltefosine AT penaimanol unravellingtherateofactionofhitsintheleishmaniadonovaniboxusingstandarddrugsamphotericinbandmiltefosine AT martinjulio unravellingtherateofactionofhitsintheleishmaniadonovaniboxusingstandarddrugsamphotericinbandmiltefosine AT coteronjosem unravellingtherateofactionofhitsintheleishmaniadonovaniboxusingstandarddrugsamphotericinbandmiltefosine |