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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Autores principales:	Ana Carolina C. de Sousa, Jill M. Combrinck, Keletso Maepa, Timothy J. Egan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/83eb3cf1f04445ff916522570afe1d21
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spelling	oai:doaj.org-article:83eb3cf1f04445ff916522570afe1d212021-12-02T15:54:11ZVirtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites10.1038/s41598-020-60221-02045-2322https://doaj.org/article/83eb3cf1f04445ff916522570afe1d212020-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-60221-0https://doaj.org/toc/2045-2322Abstract 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.Ana Carolina C. de SousaJill M. CombrinckKeletso MaepaTimothy J. EganNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Ana Carolina C. de Sousa Jill M. Combrinck Keletso Maepa Timothy J. Egan
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 Portfolio
publishDate	2020
url	https://doaj.org/article/83eb3cf1f04445ff916522570afe1d21
work_keys_str_mv	AT anacarolinacdesousa virtualscreeningasatooltodiscovernewbhaematininhibitorswithactivityagainstmalariaparasites AT jillmcombrinck virtualscreeningasatooltodiscovernewbhaematininhibitorswithactivityagainstmalariaparasites AT keletsomaepa virtualscreeningasatooltodiscovernewbhaematininhibitorswithactivityagainstmalariaparasites AT timothyjegan virtualscreeningasatooltodiscovernewbhaematininhibitorswithactivityagainstmalariaparasites
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Virtual screening as a tool to discover new β-haematin inhibitors with activity against malaria parasites

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