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Computational studies in human African trypanosomiasis

- Muronzi, Tendai

Authors: Muronzi, Tendai
Date: 2023-10-13
Subjects: African trypanosomiasis , Apolipoprotein L1 , Docking , Protein-protein interactions , Homology modeling , Tetrahydrofolate dehydrogenase , Pteridine reductase
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/431883 , vital:72812 , DOI 10.21504/10962/431885
Description: Human African trypanosomiasis (HAT) is a neglected tropical disease (NTD) caused by two subspecies of the parasite, namely Trypanosoma brucei (Tb) gambiense (g-HAT) and rhodesiense (r-HAT). HAT is endemic in sub-Saharan countries, where the parasite transmission vectors, tsetse flies, breed. An estimated 70 million people remain at risk of contracting the disease, where the infection is classified as acute or chronic for g-HAT and r-HAT, respectively, with both forms ending in fatal meningoencephalitis when left untreated. Both g-HAT and r-HAT are responsible for widespread fatal epidemics throughout sub-Saharan African history, resulting from the complex molecular interplay between trypanosomes and humans through unique, innate immunity evasion mechanisms. Of interest, the Tbr subspecies expresses a serum resistance-associated protein (SRA), which binds to human serum lytic factor, apolipoprotein L1 (ApoL1), nullifying any trypanocidal activity. In response, ApoL1 (G1 and G2) variants found in humans of sub-Saharan African lineage have been cited for conferring resistance to the r-HAT infection in an interaction that is not fully elucidated In the event of successful infection, current HAT chemotherapeutics are plagued with complexity of administration, poor efficacy, toxicity, and potential drug resistance, highlighting a need for improved approaches. The parasite folate pathway provides a strategic target for alternative anti-trypanosomal drug development as trypanosomatids are folate auxotrophs, requiring host folate for growth and survival. Validated drug targets pteridine reductase (TbPTR1) and dihydrofolate reductase (TbDHFR) are essential for salvaging cofactors folate and folate biopterin crucial to parasite survival, making them viable targets for anti-folate investigation. The overall aims of this thesis were to a) provide insights into the molecular and dynamic basis of the SRA and ApoL1 interplay in HAT infection and b) identify safer and more efficient anti-folate anti-trypanosomal drug alternatives through in silico approaches. To achieve our first aim, in silico structure prediction was applied to generate 3D models of ApoL1 C-terminal variants G0, G1, G1G/M, G2 and G1G2, and four SRA variants retrieved from the NCBI database. The SRA and ApoL1 structures were inspected dynamically to identify the effect of the variants through molecular dynamics (MD) simulations. Dynamic residue network (DRN) analysis of MD trajectories was fundamental in identifying residues playing a vital role in the intramolecular communication of both proteins in the presence of mutations. Protein-protein docking was then applied to calculate plausible SRA-ApoL1 C-terminal wild-type complex structures to further elucidate the nature of SRA-mediated infection. Through MD simulations, twelve SRA-ApoL1 dimeric structures were narrowed down from five to two energetically sound complexes. The two feasible SRA-ApoL1 complexes (1 and 2) exhibited favourable communication observed through DRN analysis, including the retaining key communication residues identified in prior monomer DRN calculations. ApoL1 C-terminal variants were additionally incorporated into SRA-ApoL1 complexes 1 and 2 for further complex dynamics analysis This investigation into the nature of SRA-ApoL1 binding resulted in five primary outcomes: 1) highlighting the intramolecular effects ApoL1 variants have on the stability of the protein, 2) the identification of crucial SRA and ApoL1 communication residues in both monomeric or dimeric form, 3) the isolation of feasible SRA-ApoL1 complexes determined through global and local structural analyses 4) identification of residues crucial to the complex formation and maintenance of SRA-ApoL1, overlapping with those identified in (1), and 5) the minimal dissociative role of the G1 mutations in the complex, but compounding effect of the G2 deletion mutation. Computational modelling and drug repurposing were employed to achieve the thesis's second aim as they drastically cut down the costs involved in drug discovery and provide a more time-efficient screening method through numerous drug candidates. Using high throughput virtual screening, a subset of 2089 approved DrugBank compounds were screened against TbPTR1. The outputs were filtered to 24 viable compounds in 54 binding poses using binding energy and molecular interactions. Through subsequent MD simulations of 200ns, thirteen potential hit compounds were identified. The resultant hit compounds were subjected to further blind docking against TbDHFR and molecular dynamics to identify compounds with the potential for dual inhibition. The filtered subset was also tested in in vitro single concentration and dose-response bioassays to assess inhibitory properties against Trypanosoma brucei, complementing in silico findings. Post-molecular dynamics, four compounds exhibited high stabilities and molecular interactions with both TbPTR1 and TbDHFR, with two presenting favourable results in the in vitro assays. Three compounds additionally shared common structural moieties. In all, the in silico repurposing highlighted drugs characterised by favourable interactions and stabilities in TbPTR1, thus providing (1) a framework for further studies investigating anti-folate HAT compounds and (2) modulatory scaffolds based on identified moieties that can be used for the design of safe anti-folate trypanosomal drugs. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2023
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Date Issued: 2023-10-13

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Using information visualization to support the self-management of type 2 diabetes mellitus

- Nauder, Meggan Kate

Authors: Nauder, Meggan Kate
Date: 2022-04
Subjects: Information visualization , Diabetics --Treatment --South Africa
Language: English
Type: Master's theses , text
Identifier: http://hdl.handle.net/10948/55711 , vital:53409
Description: The globally increasing number of individuals suffering from Type 2 Diabetes Mellitus (T2DM), a completely preventable incurable disease of the pancreas, highlights the need for an effective tool for users to understand the relationship between their behaviours and the effect that those behaviours can have on their blood glucose levels (BGLs). There are few Information Visualisation (IV) tools available that can be used to reduce the cognition required to understand correlations between behaviour and BGLs. Existing tools require time-consuming, lengthy inputs and provide simple visualisations that do not show correlations. This leads to ineffective self-management of T2DM. Information Visualisation (IV) techniques can be used to support effective self-management of T2DM and reduce the cognition required to interpret DM data. Suitable IV techniques were identified and used to visualize T2DM data to aid in the self-management of the disease. Temporal charts, i.e. The Bar, Pie and Line Chart as well as heat maps, were selected as the most appropriate IV techniques to visualize T2DM data as they support time-series data well. A prototype, MedicMetric was created as an IV tool for visualizing T2DM data. MedicMetric incorporated three designed charts, namely the Change Rate Line View, the Radial Progress View, and the Annotated Line View. The Change Rate Line View and Annotated Line View both used line IV techniques, while the Radial Progress View made use of the bar IV technique. The Change Rate Line View performed the worst overall. A usability evaluation was conducted to compare these techniques and to determine which technique is most suitable for visualizing T2DM data. The results leaned significantly in favour of the Annotated Line View. This view is most similar to the line charts typically used in other IV tools. For this reason, the MedicMetric app was briefly compared to the MySygr and Diabetes:M application. In effectiveness and efficiency, MedicMetric and MySugr obtained almost identical results. However, participants indicated that MedicMetric supported their tasks using the Visual Information Seeking Mantra (VISM) the best overall, with 100% of participants stating that they would prefer to use the MedicMetric application. Several usability problems were identified with the IV techniques and they were addressed shortly after the study was complete. Overall participants were most satisfied with the Annotated Line View. , Thesis (MSc) -- Faculty of Science, Computing Sciences, 2022
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Date Issued: 2022-04

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