Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites
Abstract
:1. Introduction
2. Results and Discussion
2.1. In Vitro Assays of the USFDA Approved Drugs
2.2. Structure-Based Virtual Screening Against the β-haematin Crystal
2.3. Haem Fractionation Assay
2.4. Ligand-Based Virtual Screening Using Lapatinib and Nilotinib as Templates for Shape and Eletrostatic Similarity
3. Materials and Methods
3.1. Compounds
3.2. Detergent Mediated Assay for β-haematin Inhibition
3.3. Plasmodium Lactate Dehydrogenase (pLDH) Assay
3.4. Structure-based Virtual Screening against the β-haematin Crystal
3.5. Haem Fractionation Assay
3.6. Statistical Analysis
3.7. Ligand-based Virtual Screening
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: All materials were obtained from specified commercial sources and are available for purchase. |
Bayesian Rank | Drug | β-haematin IC50 (μM) | PfNF54 IC50 (µM) | PfK1 IC50 (µM) | RI 2 |
---|---|---|---|---|---|
1 | Lapatinib | 5.43 ± 0.03 | 0.26 ± 0.07 | 0.85 ± 0.02 | 3.3 |
2 | Amodiaquine | 21 4 | NT 3 | 0.0086 5 | - |
3 | Imatinib | 99 ± 5 | 3.9 ± 0.1 | NT 3 | - |
4 | Nafarelin | 48 ± 5 | NA 1 | NT 3 | - |
5 | Nilotinib | 7 ± 1 | 0.28 ± 0.02 | 0.38 ± 0.06 | 1.4 |
6 | Antrafenine | NT 3 | NT 3 | NT 3 | - |
7 | Vapreotide | 48 ± 7 | NA 1 | NT 3 | - |
8 | Gefitinib | 20.4 ± 0.8 | 11.5 ± 0.4 | NT 3 | - |
13 | Thiabendazole | > 500 | NA 1 | NT 3 | - |
14 | Erlotinib | 17.6 ± 0.2 | 13.3 ± 0.4 | NT 3 | - |
19 | Lomitapide | 68.2 ± 0.9 | 0.56 ± 0.10 | 0.69 ± 0.14 | 1.2 |
21 | Chloroquine | 26 ± 0.3 | 0.015 ± 0.001 | 0.272 ± 0.005 | 18 |
1505 | Dantrolene | >500 | NT 3 | NT 3 | - |
1506 | Nitrendipine | >500 | NT 3 | NT 3 | - |
1508 | Nimodipine | >500 | NT 3 | NT 3 | - |
1510 | Acenocumarol | >500 | NT 3 | NT 3 | - |
Zinc Code | Binding Affinity | Drug | β-haematin IC50 (μM) | PfNF54 IC50 (µM) |
---|---|---|---|---|
zinc000001550499 | −13.4 | Cinacalcet | NA 1 | - |
zinc000052716421 | −12.9 | Flibanserin | NA 1 | - |
zinc000000601229 | −12.3 | Azelastine | NA 1 | - |
zinc000012503187 | −12.3 | Conivaptan | NA 1 | - |
zinc000022010649 | −12.2 | Panobinostat | - 2 | - |
zinc000003816514 | −12 | Rolapitant | - 2 | - |
zinc000003784182 | −12 | Adapalene | NA 1 | - |
zinc000003978005 | −12 | Dihydroergotamine | NA 1 | - |
zinc000019632618 | −12 | Imatinib | 99.0 ± 4.76 | 3.9 ± 0.14 |
zinc000000968263 | −11.9 | Cyclobenzaprine | NA 1 | - |
zinc000003816287 | −11.9 | Axitinib | NA 1 | - |
zinc000027990463 | −11.8 | Lomitapide | 68.2 ± 0.85 | 0.56 ± 0.10 |
zinc000006716957 | −11.8 | Nilotinib | 7.3 ± 1.2 | 0.28 ± 0.02 |
zinc000001530977 | −11.8 | Naftifine | NA 1 | - |
zinc000011681563 | −11.8 | Netupitant | - 2 | - |
zinc000000025958 | −11.7 | Rucaparib | NA 1 | - |
zinc000000538312 | −11.6 | Risperidone | NA 1 | - |
zinc000068202099 | −11.6 | Sonidegib | NA 1 | - |
zinc000003776633 | −11.5 | Acrivastine | NA 1 | - |
zinc000003798734 | −11.5 | Acitretin | NA 1 | - |
zinc000000968264 | −11.5 | Cyproheptadine | NA 1 | - |
zinc000000001261 | −11.4 | Desloratadine | NA 1 | - |
zinc000001550477 | −11.4 | Lapatinib | 5.43 ± 0.03 | 0.26 ± 0.07 |
zinc000003939013 | −11.3 | Fosaprepitant | NA 1 | - |
zinc000070466416 | −11.2 | Cabozantinib | - 2 | - |
zinc000001530886 | −11.2 | Telmisartan | 51.07 ± 0.67 | 4.99 ± 1.7 |
zinc000019144231 | −7.4 | (S)-Chloroquine 3 | - 2 | - |
zinc000019144226 | −8 | (R)-Chloroquine 3 | - 2 | - |
- | - | (±)-Chloroquine 3 | 26 ± 0.26 | 0.015 ± 0.001 |
Rank EON | Chemdiv Code | Structure | β-haematin IC50 (μM) | PfNF54 IC50 (µM) |
---|---|---|---|---|
Query molecule | Lapatinib | 5.43 ± 0.03 | 0.26 ± 0.07 | |
17 | F424-1065 | 353.9 ± 59.96 | 4.91 ± 0.44 | |
24 | C514-0466 | 143.55 ± 32.88 | NA 1 | |
27 | C514-0233 | 254.8 ± 59.26 | NA 1 | |
48 | G637-3522 | 290.05 ± 42.07 | NA 1 | |
54 | F731-0128 | 207.15 ± 19.02 | NA 1 | |
62 | C514-0129 | 183.5 ± 4.67 | NA 1 | |
Query molecule | Nilotinib | 7.3 ± 1.2 | 0.28 ± 0.02 | |
2 | F871-0652 | 156.15 ± 1.63 | 6.42 ± 0.57 | |
16 | F871-0649 | 373.4 ± 98.0 | 8.09 ± 0.12 | |
42 | F725-0689 | 85.73 ± 40.41 | 3.9 ± 0.14 | |
79 | G416-5459 | 100.95 ± 22.85 | NA 1 | |
80 | D444-0908 | 68.25 ± 6.41 | 3.84 ± 0.33 | |
113 | F545-1038 | 243.9 ± 11.46 | NA 1 |
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de Sousa, A.C.C.; Maepa, K.; Combrinck, J.M.; Egan, T.J. Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites. Molecules 2020, 25, 1571. https://doi.org/10.3390/molecules25071571
de Sousa ACC, Maepa K, Combrinck JM, Egan TJ. Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites. Molecules. 2020; 25(7):1571. https://doi.org/10.3390/molecules25071571
Chicago/Turabian Stylede Sousa, Ana Carolina C., Keletso Maepa, Jill M. Combrinck, and Timothy J. Egan. 2020. "Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites" Molecules 25, no. 7: 1571. https://doi.org/10.3390/molecules25071571