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Doctoral Degrees (Pharmaceutical Sciences)

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Browsing Doctoral Degrees (Pharmaceutical Sciences) by Subject "AIDS (Disease)--Treatment."

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    Diverse computational tools towards the understanding of HIV targets and design of potential drug candidates.
    Moonsamy, Suri.; Soliman, Mahmoud Elsayed Soliman.
    HIV/AIDS still remains to be a challenging epidemic infecting millions of individuals worldwide. The morbidity and mortality rates of HIV-infected patients has been well documented over the years. Despite on-going HIV/AIDS research and access to antiretroviral therapy, to date still no cure exists for this deliberating disease. In recent years, computational approaches have emerged as close counterparts to experiments in modern drug discovery process and in understanding complex biological phenomena. An array of in-silico computational techniques were implemented ranging from molecular dynamic (MD) simulations, de-novo design, hybrid structure-based and pharmacophore-based virtual screening, quantitative structure-activity relationship (QSAR), homology modeling, principle component analysis (PCA), residue interaction network analysis (RIN), substrate envelope analysis (SEA), to molecular mechanics and quantum mechanics. The first report (Chapter 4), demonstrated a unique strategy for developing dual acting inhibitors against HIV-1 protease (PR) and reverse transcriptase (RT). The designed targets exhibited binding affinities and dual inhibiting activity comparable to, and in some cases better than, known active reference drugs. The second study (Chapter 5), reported the activity of flexible hydroquinone-based compounds as non-nucleoside reverse transcriptase inhibitors (NNRTIs), as proposed by Bruccoleri, where no experimental or computational work supported his proposal. Results concluded that the novel flexible hydroquinone-based compounds showed improved binding affinity as compared to FDA-approved prototype drugs and more specifically potent potential mutant-resistant NNRT inhibitor activity. The third report (Chapter 6), explored the activity of novel CCR5 antagonists as potential HIV- 1 entry inhibitors. Ten scaffolds were identified as novel CCR5 antagonists or potential HIV-1 entry inhibitors. Furthermore, from the generated atom-based 3D-QSAR model, all of the parameters showed certain reliability and feasible predictability to help us design new and high selectivity CCR5 inhibitors. The fourth study (Chapter 7), explored the atomistic basis of why the M184I single mutation renders complete resistance of HIV-1 RT to lamivudine. Multiple molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA) and residue interaction network (RIN) analyses adequately clarified the effect of the M184I mutation on drug resistance to lamvudine. Results presented in this study verified that M184I mutation decreased drug binding affinity, distorted ligand optimum orientation in RT active site and affected the overall protein conformational landscape. The results also provided some potential clues for further design of novel inhibitors that are less susceptible to drug resistance. In the fifth study (Chapter 8), we identified potential HIV-Nef inhibitors by exploiting the structural features of B9 using an integrated computational tools framework. The top identified hit compounds demonstrated comparatively better binding affinities and relatable binding modes compared to the prototype antagonist, B9. Top identified hits were proposed as new potential novel leads targeting HIV-Nef with a detailed analysis of their respective binding modes. The sixth report (Chapter 9), aimed to reveal the dimer packing and unpacking phenomena of HIV-Nef in its apo and inhibitor bound conformations using molecular dynamic simulations. Results verified a more conformational flexible nature of HIV-Nef dimer in the absence of an inhibitor.as compared to B9 bound conformation of HIV-Nef, which was found to be more conformationally rigid with a lesser inter-dimeric association. We believe that the results obtained from these several studies could be of great benefit in the development of more effective therapeutic interventions for the treatment and cure of HIV/AIDS.
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    Exploring the buccal delivery potential of an antiretroviral drug.
    Ojewole, Elizabeth Bolanle.; Govender, Thirumala.
    Whilst antiretroviral drugs (ARVs) have significantly improved treatment of Human Immunodeficiency Virus infection and Acquired Immune Deficiency Syndrome (HIV and AIDS), several limitations exist with their oral route of administration. Several orally administered ARVs such as, didanosine, saquinavir, tenofovir and zidovudine are associated with low and erratic bioavailability due to extensive first pass effect (FPE) as well as gastrointestinal (GI) acids and enzymatic degradation. Moreover, the half-life for several ARV drugs is short, which requires frequent administration of doses leading to systemic side effects and decreased patient compliance. Alternative routes of administration, such as buccal, rectal and vaginal, are widely investigated in the literature. Buccal delivery of drugs may therefore overcome the above limitations by bypassing FPE and GI degradation, thus improving bioavailability. Furthermore, drug absorption following buccal administration is not influenced by the potential variations in the gastric emptying rate or the presence of food. However, drug absorption can be limited by low buccal permeability due to the epithelial lining the mucosa. Identifying optimal novel enhancers is paramount to designing and developing drugs as buccal delivery systems. In an attempt to explore the potential of the buccal mucosal route for the delivery of an ARV drug using didanosine (ddI) as a model drug, the aims of this study were to: 1] investigate the permeability properties of ddI across the buccal mucosa route in order to determine its suitability for development as a buccal delivery system, 2] determine the effects of novel permeation enhancers, i.e. aloe vera gel (AVgel), oleic acid (OA) and its novel synthesized oleodendrimer derivatives, on the buccal permeability of ddI, and 3] to find out (through histomorphological evaluation) whether ddI and the novel enhancers, i.e. AV gel and novel OA derivatives have any toxic effects on the buccal mucosa. The buccal mucosa was harvested from pigs, and all the excess connective tissue was surgically removed. In vitro buccal permeation experiments were undertaken using modified vertical Franz diffusion cells, with phosphate buffered saline pH 7.4 (PBS) at 37 °C. ddI was quantified at 250 nm using a validated UV spectrophotometric method. The histomorphological evaluations were undertaken using light microscopy (LM) and transmission electron microscopy (TEM). ddI permeated through the buccal mucosa and its permeability was concentration-dependent. A linear relationship (R² = 0.9557) between the concentrations and flux indicated passive diffusion as the mechanism of drug transport. AVgel, at concentrations of 0.25 to 2 %w/v, significantly enhanced ddI flux (p<0.05), with permeability enhancement ratios from 5.09 (0.25 %w/v) to 11.78 (2 %w/v), but decreased permeability at 4 and 6 %w/v. OA and its derivatives, i.e. ester (OA1E), the dicarboxylic acid (OA1A), the bicephalous dianionic surfactant (OA1ANa) and their parent compound, OA, all enhanced the buccal permeability of ddI. OA, OA1E, OA1A and OA1ANa at 1 %w/w all showed potential, with enhancement ratios (ER) of 1.29, 1.33, 1.01 and 1.72 respectively. OA1ANa at 1 %w/w demonstrated the highest flux (80.30 ± 10.37 μg cm ˉ².hr), permeability coefficient (4.01 ± 0.57 x 10 ˉ³ cm hrˉ¹) and enhancement ratio (1.72). The highest flux for ddI (144.00 ± 53.54 μg cm ˉ².hr) was reported with OA1ANa at 2 %w/w, which displayed an ER of 3.09 more than that with ddI alone (p=0.0014). At equivalent concentrations, OA1ANa (ER=3.09) had a significantly higher permeation enhancing effect than its parent OA (ER=1.54). Histomorphological studies showed that ddI did not have any adverse effects on the buccal mucosae. Ultrastructural analysis of the buccal mucosae treated with phosphate buffer saline pH 7.4 (PBS), ddI/PBS and ddI/PBS/AVgel 0.5 %w/v showed cells with normal plasmalemma, well-developed cristae and nuclei with regular nuclear envelopes. However, cells from 1, 2 and 6 %w/v AVgel-treated mucosae showed irregular nuclear outlines, increased intercellular spacing and plasmalemma crenulations. AVgel enhanced the buccal permeation of ddI and 0.05 %w/v was identified as a potentially safe and effective concentration for developing and optimizing buccal delivery systems. OA1ANa at all concentrations, except 6.0 %w/w had no adverse effects on the mucosae. OA1ANa at 2 %w/w was identified as a potentially safe concentration, and the optimal novel OA derivative that can widen the pool of fatty acid derivatives as chemical permeation enhancers for buccal drug delivery. The cellular changes, such as vacuoles formation and increased intercellular spaces, were attributed to the buccal permeation enhancing effects of AVgel and OA1ANa. The results in this study confirmed the potential of buccal delivery of ddI, identified permeability parameters of ddI across the buccal mucosa and its permeability enhancement by both AVgel and OA derivatives as novel permeation enhancers. The study showed that both OA1ANa at 2 %w/w and AVgel at 0.5 %w/v, or lower concentrations, can be used as buccal permeation enhancers to develop and optimize novel buccal delivery systems for ddI to improve ARV therapy. The novel enhancers are recommended for selection as buccal permeation enhancers, to design and optimize ddI buccal delivery systems, and application to other ARV drugs for improved therapy.