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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Main Authors: Ana Carolina C. de Sousa, Jill M. Combrinck, Keletso Maepa, Timothy J. Egan
Format: Article
Language:English
Published: Nature Publishing Group 2020-02-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-020-60221-0
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spelling 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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