Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches
Abstract The biomineral haemozoin, or its synthetic analogue β-haematin (βH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known βH crystal structure, the availability of this screening data makes the target amenable to bo...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-29273-w |
| _version_ | 1797864735486509056 |
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| author | Leah Amod Roxanne Mohunlal Nicole Teixeira Timothy J. Egan Kathryn J. Wicht |
| author_facet | Leah Amod Roxanne Mohunlal Nicole Teixeira Timothy J. Egan Kathryn J. Wicht |
| author_sort | Leah Amod |
| collection | DOAJ |
| description | Abstract The biomineral haemozoin, or its synthetic analogue β-haematin (βH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known βH crystal structure, the availability of this screening data makes the target amenable to both structure-based and ligand-based virtual screening. In this study, molecular docking and machine learning techniques, including Bayesian and support vector machine classifiers, were used in sequence to screen the in silico ChemDiv 300k Representative Compounds library for inhibitors of βH with retained activity against P. falciparum. We commercially obtained and tested a prioritised set of inhibitors and identified the coumarin and iminodipyridinopyrimidine chemotypes as potent in vitro inhibitors of βH and whole cell parasite growth. |
| first_indexed | 2024-04-09T22:58:01Z |
| format | Article |
| id | doaj.art-0e9d9577f75f4ad3b7611cf98b1a8ed3 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T22:58:01Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0e9d9577f75f4ad3b7611cf98b1a8ed32023-03-22T11:09:10ZengNature PortfolioScientific Reports2045-23222023-02-0113111010.1038/s41598-023-29273-wIdentifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approachesLeah Amod0Roxanne Mohunlal1Nicole Teixeira2Timothy J. Egan3Kathryn J. Wicht4Department of Chemistry, University of Cape TownDepartment of Chemistry, University of Cape TownDepartment of Chemistry, University of Cape TownDepartment of Chemistry, University of Cape TownDepartment of Chemistry, University of Cape TownAbstract The biomineral haemozoin, or its synthetic analogue β-haematin (βH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known βH crystal structure, the availability of this screening data makes the target amenable to both structure-based and ligand-based virtual screening. In this study, molecular docking and machine learning techniques, including Bayesian and support vector machine classifiers, were used in sequence to screen the in silico ChemDiv 300k Representative Compounds library for inhibitors of βH with retained activity against P. falciparum. We commercially obtained and tested a prioritised set of inhibitors and identified the coumarin and iminodipyridinopyrimidine chemotypes as potent in vitro inhibitors of βH and whole cell parasite growth.https://doi.org/10.1038/s41598-023-29273-w |
| spellingShingle | Leah Amod Roxanne Mohunlal Nicole Teixeira Timothy J. Egan Kathryn J. Wicht Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches Scientific Reports |
| title | Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches |
| title_full | Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches |
| title_fullStr | Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches |
| title_full_unstemmed | Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches |
| title_short | Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches |
| title_sort | identifying inhibitors of β haematin formation with activity against chloroquine resistant plasmodium falciparum malaria parasites via virtual screening approaches |
| url | https://doi.org/10.1038/s41598-023-29273-w |
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