Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites
With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/7/1571 |
| _version_ | 1827761237374533632 |
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| author | Ana Carolina C. de Sousa Keletso Maepa Jill M. Combrinck Timothy J. Egan |
| author_facet | Ana Carolina C. de Sousa Keletso Maepa Jill M. Combrinck Timothy J. Egan |
| author_sort | Ana Carolina C. de Sousa |
| collection | DOAJ |
| description | With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic haemozoin) inhibition and in vitro antimalarial activity. Here, we report the experimental evaluation of nine of the highest ranked drugs, confirming the accuracy of the model by showing an overall 93% hit rate. Lapatinib, nilotinib, and lomitapide showed the best activity for inhibition of β-haematin formation and parasite growth and were found to inhibit haemozoin formation in the parasite, providing mechanistic insights into their mode of antimalarial action. We then screened the USFDA approved drugs for binding to the β-haematin crystal, applying a docking method in order to evaluate its performance. The docking method correctly identified imatinib, lapatinib, nilotinib, and lomitapide. Experimental evaluation of 22 of the highest ranked purchasable drugs showed a 24% hit rate. Lapatinib and nilotinib were chosen as templates for shape and electrostatic similarity screening for lead hopping using the in-stock ChemDiv compound catalogue. The actives were novel structures worthy of future investigation. This study presents a comparison of different in silico methods to identify new haemozoin-inhibiting chemotherapeutic alternatives for malaria that proved to be useful in different ways when taking into consideration their strengths and limitations. |
| first_indexed | 2024-03-11T10:09:45Z |
| format | Article |
| id | doaj.art-4b3871f4e07042548a4b9a0e1ffcf607 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T10:09:45Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-4b3871f4e07042548a4b9a0e1ffcf6072023-11-16T14:36:32ZengMDPI AGMolecules1420-30492020-03-01257157110.3390/molecules25071571Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria ParasitesAna Carolina C. de Sousa0Keletso Maepa1Jill M. Combrinck2Timothy J. Egan3Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch 7701, South AfricaDepartment of Medicine, Division of Pharmacology, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South AfricaDepartment of Medicine, Division of Pharmacology, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South AfricaDepartment of Chemistry, Faculty of Science, University of Cape Town, Rondebosch 7701, South AfricaWith the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic haemozoin) inhibition and in vitro antimalarial activity. Here, we report the experimental evaluation of nine of the highest ranked drugs, confirming the accuracy of the model by showing an overall 93% hit rate. Lapatinib, nilotinib, and lomitapide showed the best activity for inhibition of β-haematin formation and parasite growth and were found to inhibit haemozoin formation in the parasite, providing mechanistic insights into their mode of antimalarial action. We then screened the USFDA approved drugs for binding to the β-haematin crystal, applying a docking method in order to evaluate its performance. The docking method correctly identified imatinib, lapatinib, nilotinib, and lomitapide. Experimental evaluation of 22 of the highest ranked purchasable drugs showed a 24% hit rate. Lapatinib and nilotinib were chosen as templates for shape and electrostatic similarity screening for lead hopping using the in-stock ChemDiv compound catalogue. The actives were novel structures worthy of future investigation. This study presents a comparison of different in silico methods to identify new haemozoin-inhibiting chemotherapeutic alternatives for malaria that proved to be useful in different ways when taking into consideration their strengths and limitations.https://www.mdpi.com/1420-3049/25/7/1571β-haematinhaemozoinvirtual screeningdockingdrug repurposing<i>Plasmodium</i> |
| spellingShingle | Ana Carolina C. de Sousa Keletso Maepa Jill M. Combrinck Timothy J. Egan Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites Molecules β-haematin haemozoin virtual screening docking drug repurposing <i>Plasmodium</i> |
| title | Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites |
| title_full | Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites |
| title_fullStr | Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites |
| title_full_unstemmed | Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites |
| title_short | Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites |
| title_sort | lapatinib nilotinib and lomitapide inhibit haemozoin formation in malaria parasites |
| topic | β-haematin haemozoin virtual screening docking drug repurposing <i>Plasmodium</i> |
| url | https://www.mdpi.com/1420-3049/25/7/1571 |
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