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It is well known that the costs associated with drug discovery are extremely high due the use of expensive in vitro methods as well as the high failure rate of drugs during clinical testing. In order to effectively fight the war against diseases such as malaria a far less expensive approach is required. Increasing the amount of in silico</i. work would decrease the amount of experiments that have to be done and so doing reduce the costs. In silico methods have the ability to predict major limiting factors in drug discovery resulting in only high quality drug molecules being subjected to clinical trials, thus increasing the probability of success. In this study a web-based chemoinformatics workspace aimed at research biologists was developed inside the FunGIMS application framework. This particular web-based chemoinformatics application was developed in the context of the FunGIMS suite of tools, specifically providing biological users with some of the most common chemoinformatics functions such as (1) the representation of chemical compounds, (2) chemical data, (3) databases and data sources, (4) structure search methods, (5) methods for calculating physical and chemical data (6) calculation of structure descriptors. The chemoinformatics module is supported by a modified version of the CHEBI database and the integration of OpenBabel and Frowns made it possible to perform analysis on molecules by means of SMILES-structures. As part of the validation of the chemoinformatics module of FunGIMS, the chemical space of the polyamine pathways in Plasmodium was explored in order to obtain a library of molecules based on similarities that could be possible lead-like compounds. This was used in a study of compounds against spermidine synthase from Plasmodium falciparum. By means of similarity and substructure searches the chemoinformatics module was able to produce molecules that are structurally similar. Additional filtering enabled a library of related molecules to be obtained, and used in a docking study. Compounds were found with high docking scores, thereby validating the effectiveness and usefulness of the chemoinformatics module of FunGIMS. Copyright / Dissertation (Msc)--University of Pretoria, 2009. / Biochemistry / unrestricted

The work described in this thesis is in three parts:. Part I deals with the metabolism of 5-p-aminobenzene-sulphonamide- 3-methylisothiazole (sulphasomizole), 5-amino-3--methylisothiazole, sulphanilamide, and some of the acetyl derivatives. A marked species difference has been found in the metabolism of sulphasomizole.

The analysis of large intact proteins and complex biological samples containing drug molecules is a common complicated task for many scientists. However, due to the importance of these molecules, there is a growing interest in pharmaceutical and medicinal research to develop rapid, highly sensitive and efficient analytical techniques. The advantages of capillary electrophoresis (CE) in combination with mass spectrometry (MS) provide a powerful analytical tool. However, further improvement and development of these techniques are required to extend their utility and to meet the challenges of selected analytes. Thus, the scope of this thesis deals with the development of novel analytical methods to achieve efficient and high performance analysis of peptides, intact proteins, digests of complex samples and basic pharmaceutical drug compounds in biological matrices. Implementation of CE for routine analysis of proteins and complex samples is constrained by the partial adsorption to the capillary wall. Consequently, the use of surface modified capillaries is required to control the surface properties and prevent analyte adsorption. In this thesis, analyte adsorption was successfully prevented using tailored covalent cationic (M7C4I) and electrostatic cationic (PVPy-Me) coatings. Rapid and efficient separations of peptides, proteins and digests of complex samples such as cerebrospinal fluids were obtained with these coatings. The M7C4I coating showed a distinct ability to handle large intact proteins with a molecular size of over 0.5 MDa. The highest peak efficiencies and surprisingly high peak stacking effects were obtained by adding salts to the protein samples. The effect of salt additives on peak efficiencies of intact proteins was further demonstrated and compared using different surface modified capillaries. Additionally, rapid CE-ESI-MS quantification of pharmaceutical drug molecules in human plasma was performed after a SCX-SPE sample preparation method using the M7C4I coating. In conclusion, the results presented in this thesis show the strong potential of CE in combination with MS using electrospray ionization (ESI) for the analysis of peptides and large intact proteins and the applicability for clinical monitoring of the levels of pharmaceutical drug molecules in human plasma with high sensitivity and efficiency. / Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 734