Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen.
Patients with clinical manifestations of leishmaniasis, including cutaneous leishmaniasis, have limited treatment options, and existing therapies frequently have significant untoward liabilities. Rapid expansion in the diversity of available cutaneous leishmanicidal chemotypes is the initial step in...
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ftdoajarticles:oai:doaj.org/article:c6139b906ed940fd9c9f303cbc69cf8b 2023-05-15T15:10:14+02:00 Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. Elizabeth R Sharlow David Close Tongying Shun Stephanie Leimgruber Robyn Reed Gabriela Mustata Peter Wipf Jacob Johnson Michael O'Neil Max Grögl Alan J Magill John S Lazo 2009-11-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000540 https://doaj.org/article/c6139b906ed940fd9c9f303cbc69cf8b EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2765639?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000540 https://doaj.org/article/c6139b906ed940fd9c9f303cbc69cf8b PLoS Neglected Tropical Diseases, Vol 3, Iss 11, p e540 (2009) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2009 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000540 2022-12-31T15:53:31Z Patients with clinical manifestations of leishmaniasis, including cutaneous leishmaniasis, have limited treatment options, and existing therapies frequently have significant untoward liabilities. Rapid expansion in the diversity of available cutaneous leishmanicidal chemotypes is the initial step in finding alternative efficacious treatments. To this end, we combined a low-stringency Leishmania major promastigote growth inhibition assay with a structural computational filtering algorithm. After a rigorous assay validation process, we interrogated approximately 200,000 unique compounds for L. major promastigote growth inhibition. Using iterative computational filtering of the compounds exhibiting > 50% inhibition, we identified 553 structural clusters and 640 compound singletons. Secondary confirmation assays yielded 93 compounds with EC(50)s < or = 1 microM, with none of the identified chemotypes being structurally similar to known leishmanicidals and most having favorable in silico predicted bioavailability characteristics. The leishmanicidal activity of a representative subset of 15 chemotypes was confirmed in two independent assay formats, and L. major parasite specificity was demonstrated by assaying against a panel of human cell lines. Thirteen chemotypes inhibited the growth of a L. major axenic amastigote-like population. Murine in vivo efficacy studies using one of the new chemotypes document inhibition of footpad lesion development. These results authenticate that low stringency, large-scale compound screening combined with computational structure filtering can rapidly expand the chemotypes targeting in vitro and in vivo Leishmania growth and viability. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 3 11 e540 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Elizabeth R Sharlow David Close Tongying Shun Stephanie Leimgruber Robyn Reed Gabriela Mustata Peter Wipf Jacob Johnson Michael O'Neil Max Grögl Alan J Magill John S Lazo Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Patients with clinical manifestations of leishmaniasis, including cutaneous leishmaniasis, have limited treatment options, and existing therapies frequently have significant untoward liabilities. Rapid expansion in the diversity of available cutaneous leishmanicidal chemotypes is the initial step in finding alternative efficacious treatments. To this end, we combined a low-stringency Leishmania major promastigote growth inhibition assay with a structural computational filtering algorithm. After a rigorous assay validation process, we interrogated approximately 200,000 unique compounds for L. major promastigote growth inhibition. Using iterative computational filtering of the compounds exhibiting > 50% inhibition, we identified 553 structural clusters and 640 compound singletons. Secondary confirmation assays yielded 93 compounds with EC(50)s < or = 1 microM, with none of the identified chemotypes being structurally similar to known leishmanicidals and most having favorable in silico predicted bioavailability characteristics. The leishmanicidal activity of a representative subset of 15 chemotypes was confirmed in two independent assay formats, and L. major parasite specificity was demonstrated by assaying against a panel of human cell lines. Thirteen chemotypes inhibited the growth of a L. major axenic amastigote-like population. Murine in vivo efficacy studies using one of the new chemotypes document inhibition of footpad lesion development. These results authenticate that low stringency, large-scale compound screening combined with computational structure filtering can rapidly expand the chemotypes targeting in vitro and in vivo Leishmania growth and viability. |
format |
Article in Journal/Newspaper |
author |
Elizabeth R Sharlow David Close Tongying Shun Stephanie Leimgruber Robyn Reed Gabriela Mustata Peter Wipf Jacob Johnson Michael O'Neil Max Grögl Alan J Magill John S Lazo |
author_facet |
Elizabeth R Sharlow David Close Tongying Shun Stephanie Leimgruber Robyn Reed Gabriela Mustata Peter Wipf Jacob Johnson Michael O'Neil Max Grögl Alan J Magill John S Lazo |
author_sort |
Elizabeth R Sharlow |
title |
Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. |
title_short |
Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. |
title_full |
Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. |
title_fullStr |
Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. |
title_full_unstemmed |
Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. |
title_sort |
identification of potent chemotypes targeting leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2009 |
url |
https://doi.org/10.1371/journal.pntd.0000540 https://doaj.org/article/c6139b906ed940fd9c9f303cbc69cf8b |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 3, Iss 11, p e540 (2009) |
op_relation |
http://europepmc.org/articles/PMC2765639?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000540 https://doaj.org/article/c6139b906ed940fd9c9f303cbc69cf8b |
op_doi |
https://doi.org/10.1371/journal.pntd.0000540 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
3 |
container_issue |
11 |
container_start_page |
e540 |
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1766341275804499968 |