Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.
Neglected tropical diseases, including diseases caused by trypanosomatid parasites such as Trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. As the current treatments for African trypanosomiasis and other similar infections are limited, new therapeutics are urgent...
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ftdoajarticles:oai:doaj.org/article:c3492418d00d4e61bd981a818f9cd3e3 2023-05-15T15:06:18+02:00 Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. Jacob D Durrant Laurence Hall Robert V Swift Melissa Landon Achim Schnaufer Rommie E Amaro 2010-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000803 https://doaj.org/article/c3492418d00d4e61bd981a818f9cd3e3 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2927429?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000803 https://doaj.org/article/c3492418d00d4e61bd981a818f9cd3e3 PLoS Neglected Tropical Diseases, Vol 4, Iss 8, p e803 (2010) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2010 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000803 2022-12-31T09:49:45Z Neglected tropical diseases, including diseases caused by trypanosomatid parasites such as Trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. As the current treatments for African trypanosomiasis and other similar infections are limited, new therapeutics are urgently needed. RNA Editing Ligase 1 (REL1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target.Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors. The predicted binding modes of the active compounds are evaluated within the context of the flexible receptor model and combined with computational fragment mapping to determine the most likely binding mechanisms. Ultimately, four new low-micromolar inhibitors are presented. Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.Pending additional optimization, the compounds presented here may serve as precursors for future novel therapies useful in the fight against several trypanosomatid pathogens, including human African trypanosomiasis, a devastating disease that afflicts the vulnerable patient populations of sub-Saharan Africa. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 4 8 e803 |
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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 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Jacob D Durrant Laurence Hall Robert V Swift Melissa Landon Achim Schnaufer Rommie E Amaro Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Neglected tropical diseases, including diseases caused by trypanosomatid parasites such as Trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. As the current treatments for African trypanosomiasis and other similar infections are limited, new therapeutics are urgently needed. RNA Editing Ligase 1 (REL1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target.Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors. The predicted binding modes of the active compounds are evaluated within the context of the flexible receptor model and combined with computational fragment mapping to determine the most likely binding mechanisms. Ultimately, four new low-micromolar inhibitors are presented. Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.Pending additional optimization, the compounds presented here may serve as precursors for future novel therapies useful in the fight against several trypanosomatid pathogens, including human African trypanosomiasis, a devastating disease that afflicts the vulnerable patient populations of sub-Saharan Africa. |
format |
Article in Journal/Newspaper |
author |
Jacob D Durrant Laurence Hall Robert V Swift Melissa Landon Achim Schnaufer Rommie E Amaro |
author_facet |
Jacob D Durrant Laurence Hall Robert V Swift Melissa Landon Achim Schnaufer Rommie E Amaro |
author_sort |
Jacob D Durrant |
title |
Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. |
title_short |
Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. |
title_full |
Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. |
title_fullStr |
Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. |
title_full_unstemmed |
Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. |
title_sort |
novel naphthalene-based inhibitors of trypanosoma brucei rna editing ligase 1. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2010 |
url |
https://doi.org/10.1371/journal.pntd.0000803 https://doaj.org/article/c3492418d00d4e61bd981a818f9cd3e3 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 4, Iss 8, p e803 (2010) |
op_relation |
http://europepmc.org/articles/PMC2927429?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000803 https://doaj.org/article/c3492418d00d4e61bd981a818f9cd3e3 |
op_doi |
https://doi.org/10.1371/journal.pntd.0000803 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
4 |
container_issue |
8 |
container_start_page |
e803 |
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1766337934647099392 |