Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.
<h4>Background</h4>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 limit...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-08-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0000803&type=printable |
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| _version_ | 1849694727489716224 |
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| 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 |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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 |
| id | doaj-art-c3492418d00d4e61bd981a818f9cd3e3 |
| institution | DOAJ |
| issn | 1935-2727 1935-2735 |
| language | English |
| publishDate | 2010-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj-art-c3492418d00d4e61bd981a818f9cd3e32025-08-20T03:19:59ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352010-08-0148e80310.1371/journal.pntd.0000803Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.Jacob D DurrantLaurence HallRobert V SwiftMelissa LandonAchim SchnauferRommie E Amaro<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0000803&type=printable |
| spellingShingle | 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. PLoS Neglected Tropical Diseases |
| title | 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_short | Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1. |
| title_sort | novel naphthalene based inhibitors of trypanosoma brucei rna editing ligase 1 |
| url | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0000803&type=printable |
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