In silico identification of selective novel hits against the active site of wild type mycobacterium tuberculosis pyrazinamidase and its mutants
- Authors: Gowo, Prudence
- Date: 2021-04
- Subjects: Mycobacterium tuberculosis , Pyrazinamide , Multidrug resistance , Antitubercular agents , Molecular dynamics , Hydrogen bonding , Ligand binding (Biochemistry) , Dynamic Residue Network
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/178007 , vital:42898
- Description: The World Health Organization declared Tuberculosis a global health emergency and has set a goal to eradicate it by 2035. However, effective treatment and control of the disease is being hindered by the emerging Multi-Drug Resistant and Extensively Drug Resistant strains on the most effective first line prodrug, Pyrazinamide (PZA). Studies have shown that the main cause of PZA resistance is due to mutations in the pncA gene that codes for the target protein Pyrazinamidase (PZase). Therefore, this study aimed to identify novel drug compounds that bind to the active site of wild type PZase and study the dynamics of these potential anti-TB drugs in the mutant systems of PZase. This approach will aid in identifying drugs that may be repurposed for TB therapy and/or designed to counteract PZA resistance. This was achieved by screening 2089 DrugBank compounds against the whole wild type (WT) PZase protein in molecular docking using AutoDOCK4.2. Compound screening based on docking binding energy, hydrogen bonds, molecular weight and active site proximity identified 47 compounds meeting all the set selection criteria. The stability of these compounds were analysed in Molecular Dynamic (MD) simulations and were further studied in PZase mutant systems of A3P, A134V, A146V, D8G, D49A, D49G, D63G, H51P, H137R, L85R, L116R, Q10P, R140S, T61P, V139M and Y103S. Generally, mutant-ligand systems displayed little deviation from the WT systems. The compound systems remained compact, with less fluctuations and more hydrogen bond interactions throughout the simulation (DB00255, DB00655, DB00672, DB00782, DB00977, DB01196, DB04573, DB06414, DB08981, DB11181, DB11760, DB13867, DB13952). From this research study, potential drugs that may be repurposed for TB therapy were identified. Majority of these drugs are currently used in the treatment of hypertension, menopause disorders and inflammation. To further understand the mutant-ligand dynamic systems, calculations such as Dynamic Residue Network (DRN) may be done. Also, the bioactivity of these drugs on Mycobacterium tuberculosis may be studied in wet laboratory, to understand their clinical impart in vivo experiments. , Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
- Date Issued: 2021-04
- Authors: Gowo, Prudence
- Date: 2021-04
- Subjects: Mycobacterium tuberculosis , Pyrazinamide , Multidrug resistance , Antitubercular agents , Molecular dynamics , Hydrogen bonding , Ligand binding (Biochemistry) , Dynamic Residue Network
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/178007 , vital:42898
- Description: The World Health Organization declared Tuberculosis a global health emergency and has set a goal to eradicate it by 2035. However, effective treatment and control of the disease is being hindered by the emerging Multi-Drug Resistant and Extensively Drug Resistant strains on the most effective first line prodrug, Pyrazinamide (PZA). Studies have shown that the main cause of PZA resistance is due to mutations in the pncA gene that codes for the target protein Pyrazinamidase (PZase). Therefore, this study aimed to identify novel drug compounds that bind to the active site of wild type PZase and study the dynamics of these potential anti-TB drugs in the mutant systems of PZase. This approach will aid in identifying drugs that may be repurposed for TB therapy and/or designed to counteract PZA resistance. This was achieved by screening 2089 DrugBank compounds against the whole wild type (WT) PZase protein in molecular docking using AutoDOCK4.2. Compound screening based on docking binding energy, hydrogen bonds, molecular weight and active site proximity identified 47 compounds meeting all the set selection criteria. The stability of these compounds were analysed in Molecular Dynamic (MD) simulations and were further studied in PZase mutant systems of A3P, A134V, A146V, D8G, D49A, D49G, D63G, H51P, H137R, L85R, L116R, Q10P, R140S, T61P, V139M and Y103S. Generally, mutant-ligand systems displayed little deviation from the WT systems. The compound systems remained compact, with less fluctuations and more hydrogen bond interactions throughout the simulation (DB00255, DB00655, DB00672, DB00782, DB00977, DB01196, DB04573, DB06414, DB08981, DB11181, DB11760, DB13867, DB13952). From this research study, potential drugs that may be repurposed for TB therapy were identified. Majority of these drugs are currently used in the treatment of hypertension, menopause disorders and inflammation. To further understand the mutant-ligand dynamic systems, calculations such as Dynamic Residue Network (DRN) may be done. Also, the bioactivity of these drugs on Mycobacterium tuberculosis may be studied in wet laboratory, to understand their clinical impart in vivo experiments. , Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
- Date Issued: 2021-04
Investigation of the comparative cost-effectiveness of different strategies for the management of multidrug-resistant tuberculosis
- Authors: Rockcliffe, Nicole
- Date: 2003
- Subjects: Tuberculosis , Multidrug resistance , Tuberculosis -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3788 , http://hdl.handle.net/10962/d1003266 , Tuberculosis , Multidrug resistance , Tuberculosis -- Treatment
- Description: The tuberculosis epidemic is escalating in South Africa as well as globally. This escalation is exacerbated by the increasing prevalence of multidrug-resistant tuberculosis (MDRTB), which is defined by the World Health Organisation (WHO) as resistance of Mycobacteria to at least isoniazid and rifampicin. Multi-drug resistant tuberculosis is estimated to occur in 1-2% of newly diagnosed tuberculosis (TB) patients and in 4-8% of previously treated patients. MDRTB is both difficult and expensive to treat, costing up to 126 times that of drug-sensitive TB. Resource constrained countries such as South Africa often lack both the money and the infrastructure to treat this disease. The aim of this project was to determine whether the performance of a systematic review with subsequent economic modelling could influence the decision making process for policy makers. Data was gathered and an economic evaluation of MDRTB treatment was performed from the perspective of the South African Department of Health. Three treatment alternatives were identified: a protocol regimen of second line anti-tuberculosis agents, as recommended in the South African guidelines for MDRTB, an appropriate regimen designed for each patient according to the results of culture and drug susceptibility tests, and non-drug management. A decision-analysis model using DATA 3.0 by Treeage® was developed to estimate the costs of each alternative. Outcomes were measured in terms of cost alone as well as the ‘number of cases cured’ and the number of ‘years of life saved’ for patients dying, being cured or failing treatment. Drug, hospital and laboratory costs incurred using each alternative were included in the analysis. A sensitivity analysis was performed on all variables in order to identify threshold values that would change the outcome of the evaluation. Results of the decision analysis indicate that the individualised regimen was both the cheaper and more cost-effective regimen of the two active treatment options, and was estimated to cost R50 661 per case cured and R2 070 per year of life saved. The protocol regimen was estimated to cost R73 609 per case cured and R2 741 per year of life saved. The outcome of the decision analysis was sensitive to changes in some of the variables used to model the disease, particularly the daily cost of drugs, the length of time spent in hospital and the length of treatment received by those patients dying or failing treatment. This modelling exercise highlighted significant deficiencies in the quality of evidence on MDRTB management available to policy makers. Pragmatic choices based on operational and other logistic concerns may need to be reviewed when further information becomes available. A case can be made for the establishment of a national database of costing and efficacy information to guide future policy revisions of the South African MDRTB treatment programme, which is resource intensive and of only moderate efficacy. However, due to the widely disparate range of studies on which this evaluation was based, the outcome of the study may not be credible. In this case, the use of a systematic review with subsequent economic modelling could not validly influence policy-makers to change the decision that they made on the basis of drug availability.
- Full Text:
- Date Issued: 2003
- Authors: Rockcliffe, Nicole
- Date: 2003
- Subjects: Tuberculosis , Multidrug resistance , Tuberculosis -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3788 , http://hdl.handle.net/10962/d1003266 , Tuberculosis , Multidrug resistance , Tuberculosis -- Treatment
- Description: The tuberculosis epidemic is escalating in South Africa as well as globally. This escalation is exacerbated by the increasing prevalence of multidrug-resistant tuberculosis (MDRTB), which is defined by the World Health Organisation (WHO) as resistance of Mycobacteria to at least isoniazid and rifampicin. Multi-drug resistant tuberculosis is estimated to occur in 1-2% of newly diagnosed tuberculosis (TB) patients and in 4-8% of previously treated patients. MDRTB is both difficult and expensive to treat, costing up to 126 times that of drug-sensitive TB. Resource constrained countries such as South Africa often lack both the money and the infrastructure to treat this disease. The aim of this project was to determine whether the performance of a systematic review with subsequent economic modelling could influence the decision making process for policy makers. Data was gathered and an economic evaluation of MDRTB treatment was performed from the perspective of the South African Department of Health. Three treatment alternatives were identified: a protocol regimen of second line anti-tuberculosis agents, as recommended in the South African guidelines for MDRTB, an appropriate regimen designed for each patient according to the results of culture and drug susceptibility tests, and non-drug management. A decision-analysis model using DATA 3.0 by Treeage® was developed to estimate the costs of each alternative. Outcomes were measured in terms of cost alone as well as the ‘number of cases cured’ and the number of ‘years of life saved’ for patients dying, being cured or failing treatment. Drug, hospital and laboratory costs incurred using each alternative were included in the analysis. A sensitivity analysis was performed on all variables in order to identify threshold values that would change the outcome of the evaluation. Results of the decision analysis indicate that the individualised regimen was both the cheaper and more cost-effective regimen of the two active treatment options, and was estimated to cost R50 661 per case cured and R2 070 per year of life saved. The protocol regimen was estimated to cost R73 609 per case cured and R2 741 per year of life saved. The outcome of the decision analysis was sensitive to changes in some of the variables used to model the disease, particularly the daily cost of drugs, the length of time spent in hospital and the length of treatment received by those patients dying or failing treatment. This modelling exercise highlighted significant deficiencies in the quality of evidence on MDRTB management available to policy makers. Pragmatic choices based on operational and other logistic concerns may need to be reviewed when further information becomes available. A case can be made for the establishment of a national database of costing and efficacy information to guide future policy revisions of the South African MDRTB treatment programme, which is resource intensive and of only moderate efficacy. However, due to the widely disparate range of studies on which this evaluation was based, the outcome of the study may not be credible. In this case, the use of a systematic review with subsequent economic modelling could not validly influence policy-makers to change the decision that they made on the basis of drug availability.
- Full Text:
- Date Issued: 2003
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