Browsing by Author "Moonsamy, Suri."

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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.
The effects of Tulbaghia violacea (wild garlic) leaf and bulb extracts on an oesophageal cancer cell line (SNO)
(2012) Moonsamy, Suri.; Myburg, Rene Bernadette.; Serumula, Metse Regina.
Ethnopharmacological relevance: Indigenous plants such as Tulbaghia violacea(TV) and Allium sativum (garlic) are traditionally used as natural remedies to treat a variety of ailments, including cancer. This study investigated the effects of TV leaf and bulb extracts and garlic extract on a cancerous oesophageal cell line (SNO). Materials and methods: The methylthiazoltetrazolium (MTT) assay was used to determine the IC50 of TV leaf (TVL) (250μg/ml) and TV bulb extracts (TVB) (25μg/ml) and garlic (500μg/ml). Extracts were treated individually and in combination for a period of 24 hours. Oxidative damage and intracellular glutathione levels were assessed using the Thiobarbituric Acid Reactive Substances (TBARS) Assay and GSH-Glo™ Luminometry Assay, respectively. The CellTiter-Glo® Luminescent Cell Viability Assay was used to assess ATP activity. Induction of apoptosis and mitochondrial membrane potential were determined via the Caspase-Glo® 3/7 Assay, Caspase-Glo® 8 Assay, Caspase-Glo® 9 Assay and JC-1 Mitoscreen Assay, respectively. Morphological apoptotic changes were determined using the Hoechst 33342 stain. Expressions of p53, PARP and NFKB activities were determined by western blotting. Results: Bulb and leaf extracts of TV increased lipid peroxidation compared to the control (p>0.05), whilst garlic and combination of TV leaf and bulb (TVB + TVL) extracts significantly decreased lipid peroxidation relative to the control (p< 0.05). Endogenous glutathione levels significantly decreased in all TV treatments compared to the control (p<0.05).However, garlic was accompanied by insignificantly increased intracellular glutathione levels compared to the control (p> 0.05). The percentages of depolarised mitochondria in all treated cells were significantly decreased compared to untreated cells (p< 0.05). ATP levels increased significantly in garlic and combination (TVB + TVL) treated cells as compared to the control (p< 0.05), yet no significant differences were noted in TVL and TVB treatments (p> 0.05). Caspase8 and caspase 9 activities significantly increased in garlic and combination treated cells relative to the control (p<0.05). A similar trend was noted for caspase 3/7 activity in garlic and combination treatments (p< 0.05). However, initiator and executioner activities in TVL (p> 0.05) and TVB (p> 0.05) treatments did not significantly differ from the control (p> 0.05). All treatments (including garlic) resulted in increased DNA fragmentation and condensation. All treatments decreased p53 expression (p< 0.05), PARP expression (p< 0.05) and NFK B expression (p>0.05) compared to the control. Conclusions: All TV extracts and garlic induces apoptosis in the oesophageal cancerous SNO cell line through changes in oxidative stress, antioxidant systems, and nuclear chromatin condensation, as well as through induction of nuclear genes and signalling pathways. Since inhibition of apoptosis is a principal alteration in cancer, induction of apoptosis would result in a decrease in cancer cell growth. Thus, TV could be exploited as a potential anti-cancer agent.