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...
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ftdoajarticles:oai:doaj.org/article:ffe29b3dbe854f72a261f72696b8de5c 2023-05-15T15:15:48+02:00 Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine. Diana Tegazzini Juan Cantizani Imanol Peña Julio Martín Jose M Coterón 2017-05-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0005629 https://doaj.org/article/ffe29b3dbe854f72a261f72696b8de5c EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5462473?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005629 https://doaj.org/article/ffe29b3dbe854f72a261f72696b8de5c PLoS Neglected Tropical Diseases, Vol 11, Iss 5, p e0005629 (2017) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2017 ftdoajarticles https://doi.org/10.1371/journal.pntd.0005629 2022-12-31T13:43:44Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 11 5 e0005629 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Diana Tegazzini Juan Cantizani Imanol Peña Julio Martín Jose M Coterón Unravelling the rate of action of hits in the Leishmania donovani box using standard drugs amphotericin B and miltefosine. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 |
Article in Journal/Newspaper |
author |
Diana Tegazzini Juan Cantizani Imanol Peña Julio Martín Jose M Coterón |
author_facet |
Diana Tegazzini Juan Cantizani Imanol Peña Julio Martín Jose M Coterón |
author_sort |
Diana Tegazzini |
title |
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_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_sort |
unravelling the rate of action of hits in the leishmania donovani box using standard drugs amphotericin b and miltefosine. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2017 |
url |
https://doi.org/10.1371/journal.pntd.0005629 https://doaj.org/article/ffe29b3dbe854f72a261f72696b8de5c |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 11, Iss 5, p e0005629 (2017) |
op_relation |
http://europepmc.org/articles/PMC5462473?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0005629 https://doaj.org/article/ffe29b3dbe854f72a261f72696b8de5c |
op_doi |
https://doi.org/10.1371/journal.pntd.0005629 |
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PLOS Neglected Tropical Diseases |
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11 |
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5 |
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e0005629 |
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