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The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors
Myburgh, Dirkie Coenraad. 2023. The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors. Unpublished doctoral dissertation. Stellenbosch : Stellenbosch University [online]. Available at: https://scholar.sun.ac....
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2023
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| _version_ | 1867613982128340992 |
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| access_status_str | Open Access |
| author | Myburgh, Dirkie Coenraad |
| author2 | De Villiers, Katherine |
| author_browse | De Villiers, Katherine Myburgh, Dirkie Coenraad |
| author_facet | De Villiers, Katherine Myburgh, Dirkie Coenraad |
| author_sort | Myburgh, Dirkie Coenraad |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Myburgh, Dirkie Coenraad. 2023. The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors. Unpublished doctoral dissertation. Stellenbosch : Stellenbosch University [online]. Available at: https://scholar.sun.ac.za/items/a0e16696-23d6-485b-a6cc-954152467be1 |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/128440 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:44:46.833Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/128440 The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors Myburgh, Dirkie Coenraad De Villiers, Katherine Egan, Timothy Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Malaria -- Chemotherapy Plasmodium falciparum Antimalarials Heme -- Metabolism UCTD Drug resistance Myburgh, Dirkie Coenraad. 2023. The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors. Unpublished doctoral dissertation. Stellenbosch : Stellenbosch University [online]. Available at: https://scholar.sun.ac.za/items/a0e16696-23d6-485b-a6cc-954152467be1 Thesis (PhD)--Stellenbosch University, 2023. ENGLISH ABSTRACT: Plasmodium falciparum resistance to antimalarial drugs continues to threaten campaigns to eradicate malaria. Thus, there is a pressing demand to introduce new hits and lead compounds into the drug development pipeline. While traditional high-throughput screening is time-consuming and resource intensive, in silico methods tend to require a level of expertise and software tools that are not always readily available. Thus, there is still a need for simple and cost-effective predictive methods that can increase the probability of identifying inhibitors and lead compounds. The asexual blood stage of the malaria parasite, in particular the heme detoxification (HD) pathway, is a validated target for several clinical antimalarial drugs. In this thesis a twofold aim was pursued. Firstly, a series of principal component analysis (PCA) based two-dimensional maps of antiplasmodium chemical space was created. The Tres Cantos Antimalarial set was used as a representative compound set along with descriptor sets resulting in good Kaiser-Meyer-Olkin scores (≥ 0.8) and % cumulative variances (≥ 70%). The maps were trained with known β-hematin inhibition data, after which the best map was selected and used for the identification of new β-hematin inhibitors. Three β regions, β3, β2 and β1 were identified on the map, with respective predicted hit-rates of 8.8, 2.0 and 0.4%. From the respective regions, 24, 44 and 19 new compounds were identified, purchased, and tested for β-hematin inhibition activity. Respective hit-rates of 33% (16/24), 20% (9/44) and 16% (3/19) were obtained, maintaining a similar trend as the predicted hit--rates. This also illustrates considerable enrichment compared to random screening for inhibitors (<1%). The most active compound, B37, contains a pyrido carbazole and demonstrated potent β-hematin inhibitory activity (IC50 = 6.4 +/- 0.19), and noteworthy activity against the chloroquine-sensitive NF54 strain (IC50 = 0.32 +/- 0.03 μM). Secondly, a series of ordinary differential equation-based mathematical models of the heme detoxification pathway were constructed based on current known experimental knowledge and data concerning the pathway. Four models of increasing complexity were constructed that predict the levels of heme-Fe from hemoglobin (Hb), free (unbound) heme and hemozoin (HZ) over the parasite life-cycle and compared to known experimental heme fractionation data of the heme-Fe levels in the Dd2 parasite strain. For model 4, respective R2 values of <0, 0.86 and 0.98 was obtained when comparing the modelled Hb, free heme and HZ levels to experimental data. The models were able to predict the levels of free heme and HZ but not the levels of Hb. In a fifth model the effect of various drugs on the heme-Fe levels were modelled as a function of drug concentration and compared to experimental heme fractionation data of drug treated parasites from the D10 and NF54 strain. Although poor fits were obtained, visually the modelled free heme and HZ levels follow a similar, decreasing-logarithmic, trend as the experimental data. These models reveal areas where knowledge of the pathway is still limited and brings us closer to a model system that can be interrogated and used for the validation of new drugs. AFRIKAANSE OPSOMMING: Plasmodium falciparum weerstand teen malaria teenmiddels dreig steeds veldtogte om malaria uit te roei. Dus is daar 'n dringende aanvraag daarna om nuwe voorloperverbindings aan die dwelmontwikkelingspyplyn bekend te stel. Tradisionele sifting van verbindings deur eksperimentele hoë-deurvloei toetse is tydrowend en hulpbronintensief, terwyl in silico-metodes 'n vlak van kundigheid en sagteware-instrumente vereis wat nie altyd geredelik beskikbaar is nie. Dus is daar steeds 'n behoefte aan eenvoudige, koste-effektiewe voorspellingsmetodes wat die waarskynlikheid kan verhoog om inhibeerders en voorloperverbindings te identifiseer. Die bloedstadium van die malariaparasiet, veral die heem-ontgiftingspadweg, is 'n bevestigde teiken vir verskeie kliniese malaria teenmiddels. In hierdie tesis is 'n tweeledige doel nagestreef. Eerstens is 'n reeks hoofcomponent analise (HKA) gebaseerde tweedimensionele kaarte van antiplasmodium chemiese ruimte geskep. Die Tres Cantos Antimalaria verbindingstel is gebruik as 'n verteenwoordigende stel saam met beskrywende veranderlikes wat goeie Kaiser-Meyer-Olkin (≥ 0.8) en % kumulatiewe variansie (≥ 70%) waardes tot gevolg het. Nadat bestaande β-hematien inhiberingsdata gebruik is om die kaarte op te lei, is die beste kaart gekies en gebruik om nuwe β-hematien inhibeerders te identifiseer. Drie β-areas, β3, β2 en β1 is op die kaart geïdentifiseer, met onderskeie voorspelde trefkoerse van 8.8, 2.0 en 0.4%. Vanuit die onderskeie areas is 24, 44 en 19 nuwe verbindings geïdentifiseer, aangekoop en getoets vir β-hematien inhiberingsaktiwiteit. Onderskeie trefkoerse van 33% (16/24), 20% (9/44) and 16% (3/19) is verkry, en dus word 'n soortgelyke tendens gehandhaaf as wat voorspel is. Dit illustreer ook aansienlike verryking in vergelyking met lukrake toetsing vir inhibeerders (<1%). Die mees aktiewe verbinding, B37, bevat 'n pirido-karbasool en toon sterk β-hematien-inhiberingsaktiwiteit (IC50 = 6.4 +/- 0.19) en noemenswaardige aktiwiteit teen die chloroquine-sensitiewe NF54 parasietstam (IC50 = 0.32 +/- 0.03 μM). Doctoral 2023-02-06T19:17:40Z 2023-08-30T13:08:31Z 2023-02-06 2023-02-06T19:17:40Z 2023-08-31T09:18:43Z 2023-02-06T19:17:40Z 2023-08-31T09:18:43Z 2023-02 Thesis https://scholar.sun.ac.za/handle/10019.1/128440 en Stellenbosch University application/pdf xx, 224 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Malaria -- Chemotherapy Plasmodium falciparum Antimalarials Heme -- Metabolism UCTD Drug resistance Myburgh, Dirkie Coenraad The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors |
| title | The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors |
| title_full | The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors |
| title_fullStr | The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors |
| title_full_unstemmed | The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors |
| title_short | The heme detoxification pathway : towards the development of a predictive model for the identification and validation of new β hematin inhibitors |
| title_sort | heme detoxification pathway towards the development of a predictive model for the identification and validation of new β hematin inhibitors |
| topic | Malaria -- Chemotherapy Plasmodium falciparum Antimalarials Heme -- Metabolism UCTD Drug resistance |
| url | https://scholar.sun.ac.za/handle/10019.1/128440 |
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