Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites
Abstract 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-haemat...
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2020-02-01
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Online Access: | https://doi.org/10.1038/s41598-020-60221-0 |
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doaj-83eb3cf1f04445ff916522570afe1d212021-03-11T12:36:13ZengNature Publishing GroupScientific Reports2045-23222020-02-0110111010.1038/s41598-020-60221-0Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasitesAna Carolina C. de Sousa0Jill M. Combrinck1Keletso Maepa2Timothy J. Egan3University of Cape Town, Department of ChemistryUniversity of Cape Town, Division of Pharmacology, Department of MedicineUniversity of Cape Town, Division of Pharmacology, Department of MedicineUniversity of Cape Town, Department of ChemistryAbstract 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.https://doi.org/10.1038/s41598-020-60221-0 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Carolina C. de Sousa Jill M. Combrinck Keletso Maepa Timothy J. Egan |
spellingShingle |
Ana Carolina C. de Sousa Jill M. Combrinck Keletso Maepa Timothy J. Egan Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites Scientific Reports |
author_facet |
Ana Carolina C. de Sousa Jill M. Combrinck Keletso Maepa Timothy J. Egan |
author_sort |
Ana Carolina C. de Sousa |
title |
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_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_sort |
virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2020-02-01 |
description |
Abstract 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. |
url |
https://doi.org/10.1038/s41598-020-60221-0 |
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