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Identification and evaluation of novel inhibitors to target plasmodium falciparum
Thesis (MSc)--Stellenbosch University, 2021.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2021
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| _version_ | 1867613830584991744 |
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| access_status_str | Open Access |
| author | Thibaud, Jessica Leigh |
| author2 | De Villiers, Katherine A. |
| author_browse | De Villiers, Katherine A. Thibaud, Jessica Leigh |
| author_facet | De Villiers, Katherine A. Thibaud, Jessica Leigh |
| author_sort | Thibaud, Jessica Leigh |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2021. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/110570 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:42:21.587Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/110570 Identification and evaluation of novel inhibitors to target plasmodium falciparum Thibaud, Jessica Leigh De Villiers, Katherine A. Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science. Plasmodium falciparum Antimalarial agents Pharmaceutical chemistry UCTD Thesis (MSc)--Stellenbosch University, 2021. ENGLISH ABSTRACT: The β-haematin Inhibitor Chemical Space (βICS) map was initially developed in our research group as a means to improve the hit rate of identifying new β-haematin inhibitors compared to when a compound is selected at random. The work presented in this dissertation aims to assess the ability of this map to be used for the investigation of various other druggable targets within the malaria parasite, including dihydroorotate dehydrogenase (PfDHODH) and cGMP-dependent protein kinase (PfPKG). Hence, the first part of this work focussed on collecting inhibitor data for numerous Plasmodium falciparum drug targets, followed by evaluation of these compounds in two-dimensional antimalarial chemical space. This was carried out with the same principal component analysis (PCA) approach used to generate the βICS map. Three distinct clusters were observed on the βICS map relating to P. falciparum kinase, protease and electron transport chain inhibitors. The PfDHODH enzyme of the parasite was selected for further investigation from the electron transport inhibitor cluster, primarily due to the availability of active and inactive compound data which enabled the generation of a target-specific percentage enrichment map. This new map, showing distinct regions of active and inactive compound enrichment, was used in combination with a ligand-receptor docking investigation to predict the PfDHODH inhibitory activity of a number of compounds with unknown activities. Thereafter, predicted active and inactive compounds were biologically evaluated to validate these model predictions. Overall, two predicted active compounds, JT01 and JT06, were identified showing promising enzyme inhibition activities and IC50 values of 0.91 μM and 0.17 μM, respectively. This gives a significant hit rate of 40.0 % when the percentage map is used alongside a docking score cutoff constraint of -10.0 kcal/mol to identify new PfDHODH inhibitors. These results prompted a similar investigation of a second target, and since the kinase inhibitors also displayed considerable clustering on the βICS map, PfPKG was selected. A major restriction of this study, however, was that known inactive data were significantly limited. Therefore, it was not possible initially to generate a percentage enrichment map. Consequently, the βICS map was used in combination with a docking study to identify new PfPKG inhibitors. Unfortunately, this proved to be unsuccessful with no predicted active compounds showing > 40.0% enzyme inhibition. Soon after, it became possible to create a PfPKG percentage enrichment map as a result of data sharing via our collaboration with H3D. This map visibly validated the inactivity of the previously tested compounds and was used to guide a new selection of predicted inhibitors which are currently undergoing evaluation. These findings indicate the importance of using enrichment maps alongside molecular modelling to identify new inhibitors of the malaria parasite. In particular, two new inhibitors of PfDHODH were identified using this method, demonstrating its potential to serve the medicinal chemistry community. AFRIKAANSE OPSOMMING: Die β-hematien Inhibeerder Chemiese Ruimte (βICR) kaart was aanvanklik ontwikkel, in ons groep, om ‘n verbeterde trefkoers te behaal, in die identifisering van nuwe verbindings wat β-hematien inhibeerders is, in vergelyking met wanneer verbindings ewekansig gekies word. Die werk wat in hierdie dissertasie aangebied word beoog om die kaart se vermoë te evalueer in die analise van verskeie ander teikens binne die malaria parasiet insluitend dihidroorotaat dehidrogenaas en cGMP-afhanklike proteïen kinese (PfPKG). Dus fokus die eerste gedeelte van die werk op die insameling van verbinding-inhibeerder data vir verskeie Plasmodium falciparum teikens waarna die evaluasie van hierdie verbindings in die twee-dimensionele anti-malaria chemiese ruimte plaasvind. Dieselfde hoofkomponentontleding (HK) benadering was gebruik in hierdie evaluasie as wat gebruik was om die βICR kaart te genereer. Drie onderskeie groeperings van verbindings, verwant aan P. falciparum kinese, protease en elektronvervoerkettinginhibeerders, was waargeneem op die βICR kaart. Die PfDHODH ensiem, vanaf die elektronvervoerinhibeerder groep, was geselekteer vir verdere ondersoek weens die beskikbaarheid van aktief en onaktiewe verbinding data wat dit moontlik maak om ‘n teikenspesifieke persentasieverrykingskaart te genereer. Hierdie nuwe kaart, met onderskeie verrykte areas van aktief en onaktiewe verbindings, was gebruik in kombinasie met ‘n ligand-reseptor dokkingsanalisie om die PfDHODH inhiberingsaktiwiteite van ‘n reeks verbindings met onbekende aktiwiteite te voorspel. Daarna was hierdie verbindings biologies getoets om die voorspellings te beproef. Algeheel was twee voorspelde aktiewe verbindings, JT01 en JT06, met belowende ensiem-inhiberingsaktiwiteite en onderskeie IC50 waardes van 0.91 μM en 0.17 μM, geïdentifiseer. Met die gebruik van die persentasie kaart, tesame met ‘n dokkings-telling afsnypunt van -10.0 kcal/mol, was ‘n indrukwekkende trefkoers van 40.0% verkry in die identifisering van nuwe PfDHODH inhibeerders. Weens hierdie resultate, en aangesien die kinese inhibeerders ook aansienlike groepering toon op die βICR kaart, was ‘n tweede teiken, PfPKG, geselekteer vir ‘n soortgelyke studie. ‘n Beperking van hierdie studie was egter dat onaktiewe verbinding data baie beperk was en dus was dit aanvanklik nie moontlik om ‘n persentasieverrykingskaart te genereer nie. Gevolglik was die βICR kaart gebruik in kombinasie met ‘n dokkingsanalisie om nuwe PfPKG inhibeerders te identifiseer. Geen van die voorspelde aktiewe verbindings het egter ensiem inhibering >40.0% getoon nie. Kort hierna het dit wel moontlik geword om ‘n PfPKG persentasieverrykingskaart te genereer weens data verlening via ons samewerking met H3D. Die kaart het die onaktiwiteit van die vorige getoetste verbindings bevestig en was gebruik in die seleksie van ‘n nuwe stel voorspelde inhibeerders, wat huidiglik onder evaluasie is. Hierdie bevindinge dui op die belangrikheid daarvan om verrykingskaarte te gebruik, tesame met molekulêre modellering, in die identifisering van nuwe inhibeerders van die malaria parasite. Die identifisering van twee nuwe inhibeerders van PfDHODH demonstreer die potensiaal in die gebruik van hierdie metodes binne die medisinale chemie gemeenskap. Masters 2021-06-07T14:01:26Z 2021-06-07T14:01:26Z 2021-03 Thesis http://hdl.handle.net/10019.1/110570 en Stellenbosch University xii, 198 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Plasmodium falciparum Antimalarial agents Pharmaceutical chemistry UCTD Thibaud, Jessica Leigh Identification and evaluation of novel inhibitors to target plasmodium falciparum |
| title | Identification and evaluation of novel inhibitors to target plasmodium falciparum |
| title_full | Identification and evaluation of novel inhibitors to target plasmodium falciparum |
| title_fullStr | Identification and evaluation of novel inhibitors to target plasmodium falciparum |
| title_full_unstemmed | Identification and evaluation of novel inhibitors to target plasmodium falciparum |
| title_short | Identification and evaluation of novel inhibitors to target plasmodium falciparum |
| title_sort | identification and evaluation of novel inhibitors to target plasmodium falciparum |
| topic | Plasmodium falciparum Antimalarial agents Pharmaceutical chemistry UCTD |
| url | http://hdl.handle.net/10019.1/110570 |
| work_keys_str_mv | AT thibaudjessicaleigh identificationandevaluationofnovelinhibitorstotargetplasmodiumfalciparum |