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Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites
Malaria remains a major public health problem. With the loss of antimalarials to resistance, the malaria burden will likely continue for decades. New antimalarial scaffolds are crucial to avoid cross-resistance. Here, we present the first structure based virtual screening using the β-haematin crysta...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042288/ https://www.ncbi.nlm.nih.gov/pubmed/32099045 http://dx.doi.org/10.1038/s41598-020-60221-0 |
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author | de Sousa, Ana Carolina C. Combrinck, Jill M. Maepa, Keletso Egan, Timothy J. |
author_facet | de Sousa, Ana Carolina C. Combrinck, Jill M. Maepa, Keletso Egan, Timothy J. |
author_sort | de Sousa, Ana Carolina C. |
collection | PubMed |
description | Malaria remains a major public health problem. With the loss of antimalarials to resistance, the malaria burden will likely continue for decades. New antimalarial scaffolds are crucial to avoid cross-resistance. Here, we present the first structure based virtual screening using the β-haematin crystal as a target for new inhibitor scaffolds by applying a docking method. The ZINC15 database was searched for compounds with high binding affinity with the surface of the β-haematin crystal using the PyRx Virtual Screening Tool. Top-ranked compounds predicted to interact with β-haematin were submitted to a second screen applying in silico toxicity and drug-likeness predictions using Osiris DataWarrior. Fifteen compounds were purchased for experimental testing. An NP-40 mediated β-haematin inhibition assay and parasite growth inhibition activity assay were performed. The benzoxazole moiety was found to be a promising scaffold for further development, showing intraparasitic haemozoin inhibition using a cellular haem fractionation assay causing a decrease in haemozoin in a dose dependent manner with a corresponding increase in exchangeable haem. A β-haematin inhibition hit rate of 73% was found, a large enrichment over random screening, demonstrating that virtual screening can be a useful and cost-effective approach in the search for new haemozoin inhibiting antimalarials. |
format | Online Article Text |
id | pubmed-7042288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70422882020-03-03 Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites de Sousa, Ana Carolina C. Combrinck, Jill M. Maepa, Keletso Egan, Timothy J. Sci Rep Article Malaria remains a major public health problem. With the loss of antimalarials to resistance, the malaria burden will likely continue for decades. New antimalarial scaffolds are crucial to avoid cross-resistance. Here, we present the first structure based virtual screening using the β-haematin crystal as a target for new inhibitor scaffolds by applying a docking method. The ZINC15 database was searched for compounds with high binding affinity with the surface of the β-haematin crystal using the PyRx Virtual Screening Tool. Top-ranked compounds predicted to interact with β-haematin were submitted to a second screen applying in silico toxicity and drug-likeness predictions using Osiris DataWarrior. Fifteen compounds were purchased for experimental testing. An NP-40 mediated β-haematin inhibition assay and parasite growth inhibition activity assay were performed. The benzoxazole moiety was found to be a promising scaffold for further development, showing intraparasitic haemozoin inhibition using a cellular haem fractionation assay causing a decrease in haemozoin in a dose dependent manner with a corresponding increase in exchangeable haem. A β-haematin inhibition hit rate of 73% was found, a large enrichment over random screening, demonstrating that virtual screening can be a useful and cost-effective approach in the search for new haemozoin inhibiting antimalarials. Nature Publishing Group UK 2020-02-25 /pmc/articles/PMC7042288/ /pubmed/32099045 http://dx.doi.org/10.1038/s41598-020-60221-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article de Sousa, Ana Carolina C. Combrinck, Jill M. Maepa, Keletso Egan, Timothy J. Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
title | Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
title_full | Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
title_fullStr | Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
title_full_unstemmed | Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
title_short | Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
title_sort | virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042288/ https://www.ncbi.nlm.nih.gov/pubmed/32099045 http://dx.doi.org/10.1038/s41598-020-60221-0 |
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