https://cris.library.msu.ac.zw//handle/11408/2839 2026-04-07T03:45:15Z https://cris.library.msu.ac.zw//handle/11408/6366 Title: Discovery of gamma-secretase inhibitors for breast cancer therapy through chemogenomic methods Authors: Ngceboyakwethu Primrose Zinyama Abstract: Breast cancer recurrence is often treated with hormonal and targeted chemotherapy. To this end, nicastrin, a protein involved in Notch signaling, has been associated with breast cancer recurrence. In this work, binding sites in nicastrin were identified. Binding interactions, and modes, of known nicastrin inhibitors were investigated using structure-based techniques. A binding site, termed the DYIGS binding site, (named after the conserved hydrophilic residues Asp336, Tyr337, Iso338, Gly339, and Ser340 found in the site) was identified. The binding mechanisms, and interactions, of known nicastrin inhibitors were investigated in the identified binding sites. This was done using binding free energy calculations, and per residue decomposition analysis. Residues such as Val138, Gln139. Asp143, Arg105 and Glu174 were discovered to be important in the interactions. The physicochemical properties and scaffold space of nicastrin inhibitors were investigated. Scaffold analysis and machine learning models identified specific connectivity containing a sulfon, sulfonamide, or sulfonamide connected to cyclic structures; and a halide or a halide connected to a benzene ring as being associated with high activity for nicastrin inhibition. Seven nicastrin inhibitors were discovered using this information. A preliminary antitumour bioassay confirmed the activity of six of the seven compounds, which inhibited tumour growth by more than 20%. However, three of these compounds demonstrated acceptable physicochemical and pharmacokinetic properties. The identification of these nicastrin actives opens new avenues for the development of breast cancer treatments. 2023-10-18T00:00:00Z Ngceboyakwethu Primrose Zinyama https://cris.library.msu.ac.zw//handle/11408/4903 Title: Enhancing the Fight against Malaria: From Genome to Structure and Activity of a G-Protein Coupled Receptor from the Mosquito, Anopheles Gambiae. Authors: Mugumbate, Grace Chitima Abstract: Enhancing the Fight against Malaria: From Genome to Structure and Activity of a G-Protein Coupled Receptor in the Mosquito, Anopheles Gambiae Grace Chitima Mugumbate Department of Chemistry, University of Cape Town, Private Bag, Rondebosch, 7701, South Africa. Submitted March 2010 G-proton coupled receptors (GPCRs) are excellent drug targets that occupy a central position in the physiology of insects and are involved in transmission of signal from the extracellular to the intracellular side of the cell. Adipokinetic hormone receptors (AKHRs) are GPCRs that mediate physiological functions of the neurohormones, adipokinetic hormones (AKHs) that regulate mobilisation of energy reserves during mosquito flight. Ligand binding to GPCRs depends on the three dimensional (3D) structures of the receptors but to date no crystal structures of insect GPCRs are available. This work focused on building molecular models of AKHR from the genome of the malaria mosquito, identifying its binding site and studying the conformational and structural changes during molecular dynamics of the active and inactive receptor. Homology modelling was used to build the helices based on the crystal structures of rhodopsin and beta2-adrenergic receptor (β2AR). The loops were built separately and joined to their respective helices. Molecular dynamics was used for conformational search of the loops. The two resulting 3D structures of the GPCR from the malaria mosquito had similar overall structures. However, the β2AR-based structure had an ‘open’ conformation in the extracellular region, whilst the rhodopsinbased model was ‘closed’. NMR restrained molecular dynamics was used to determine the solution conformation of AKH-I from Anopheles gambiae (Anoga_akh). Docking calculations of this peptide and the decapeptide, Del_CC, from the blister beetle showed that helices 2,3,5,6, and 7, and the extracellular domains defined the binding pocket of AKHR. The ‘open’ AKHR model provided easy access to the binding site and had higher affinity for the ligands than the ‘closed’ structure. During molecular dynamics, after binding of the agonist, the receptor binding pocket closed to protect the ligand. At the same time the intracellular region opened. Although conversion of the receptor from inactive to active state was slow with Anoga_akh, the receptor had a higher affinity for the ligand than for Del_CC as indicated by estimated free energy of binding, -47.3 kJ/mol and -38.5 kJ/mol respectively. The protein-ligand complexes were stabilised by an intense network of H-bonds, salt bridges and hydrophobic interactions. Tyr285 (H6) played an important role in binding Del_CC, whilst ILe106 (H2) was pivotal in binding Anoga_akh. Since AKHR facilitates energy mobilisation during insect flight, knowledge of the 3D structure and binding pocket of the receptor from the malaria mosquito could lead to structure-based design of non peptide antagonists that prevent binding of AKH molecules. This would stop generation of energy for the mosquito to fly and pave the way for development of insect specific insecticides and reduction of transmission of malaria 2010-01-01T00:00:00Z Mugumbate, Grace Chitima https://cris.library.msu.ac.zw//handle/11408/4538 Title: Catalytic conversion of carbon dioxide to formate using novel metal organic frameworks Authors: Tshuma, Piwai Abstract: The combustion of fossil fuels has significantly increased the concentration of carbon dioxide (CO2) in the atmosphere. CO2 is a greenhouse gas and a major contributor to global warming. To rectify the CO2 problem, its capture and conversion have been proposed. Metal-organic framework (MOF) based materials, a relatively new class of porous materials, with unique structural features, high surface area, chemical tenability and stability, have been extensively studied for various applications. Advances in the design of these materials, including functionalisation of the linker with catalytically active species, add to the variation in the structures, providing a further means of tailoring MOF properties. In this thesis, a series of MOFs, prepared from 2,2’-bipyridine-4,4’-dicarboxylate linker with LaIII, MnII, MgII, CdII and ZnII are presented. The choice of the linker was to allow MOF formation through the carboxylate moiety while the bipyridyl units act as anchoring sites for catalytically active metals such as RuII and PdII. Structural elucidation of the compounds was performed by single crystal X-ray diffraction. The topological analysis was performed on the networks to get a better understanding of network connectivity. Bulk material was characterised using thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), scanning electron microscopy energy dispersive spectroscopy (SEM-EDS), X-ray photoelectron spectroscopy, high resolution transmission electron microscopy (HR-TEM) and nuclear magnetic resonance spectroscopy (NMR). The topological analysis revealed that the MOF constructed using LaIII, JMS-1 (Johannesburg and Midlands State) had a new network topology, zaz (South Africa and Zimbabwe). The porosity of the activated phases was tested using CO2 (298, 273, 195 K), nitrogen (77 K) and hydrogen (77 K) sorption experiments. CO2 sorption experiments on JMS-1a, Ru(II)@JMS-1a, JMS-3a and JMS-4a showed a Type I isotherm, which is typical of microporous materials. The hydrogenation of CO2 to formate was performed under various conditions (solvent, base, temperature, pressure, time and catalyst loading) to establish the optimum conditions. The formate product was detected and quantified by 1H NMR spectroscopy, with acetone as an internal standard. The functionalised MOFs, Ru(II)@JMS-1a, Pd@Mn: JMS-2a and Pd@Mg: JMS-2a displayed excellent catalytic hydrogenation of CO2 under mild conditions. On the contrary, the native MOF, JMS-1a required harsh conditions to produce significant yields of formate. This work demonstrates that the catalytic activity of homogeneous systems can be enhanced under heterogeneous conditions by incorporating them in the MOFs. 2020-01-01T00:00:00Z Tshuma, Piwai https://cris.library.msu.ac.zw//handle/11408/2840 Title: Crystal engineering of dynamic metal-organic frameworks for applications in chromic sensing and capturing of small molecules Authors: Mehlana, Gift Abstract: Crystal engineering of metal organic frameworks (MOFs) has developed rapidly over the years. This has been fuelled by useful properties endowed by these materials. MOFs present a unique platform to control chemical and physical properties through manipulation of the components that construct these materials. In this thesis a series of MOFs prepared from 3-(4-pyridyl)benzoate or 4-(4-pyridyl)benzoate with Co(ll), Zn(ll) and Ni(ll) are presented. Most materials were synthesised under solvothermal conditions. The link between the phenyl and pyridyl ring in the ligand allows for conformational change through varying the dihedral angles between these two parts. The carboxylate moiety can also rotate relative to the phenyl ring and its ability to assume different coordination modes under different environments is of utmost importance in achieving flexibility for the design. Structural elucidation of compounds was performed by single crystal X-ray diffraction. Topological analysis was performed on the networks formed by the compounds to have a better understanding of the network connectivity. Bulk material was characterised by thermal methods such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), variable temperature powder X-ray diffraction (PXRD) studies and by hot stage microscopy (HSM). Thermochromic and solvatochromic properties of the activated phases were investigated by spectroscopic techniques. Dynamic motion of the networks upon guest loss and absorption by activated phases were evaluated by single crystal X-ray diffraction studies using Pawley fitting methods. Standard kinetic models were used to analyse the kinetics of guest uptake from isothermal experiments. Non-isothermal experiments were conducted using the TGA and the activation energies were determined for guest desolvation using the Ozawa and Flynn method. 2014-01-01T00:00:00Z Mehlana, Gift