Structural analysis of effects of mutations on HIV-1 subtype C protease active site

Mathu, Alexander Muchugia Ng'anga (2012) Structural analysis of effects of mutations on HIV-1 subtype C protease active site. Masters thesis, Rhodes University.

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Abstract

HIV/AIDS is a global pandemic that poses a great threat especially in Sub-Saharan Africa where the highest population of those infected with the virus is found. It has far reaching medical, socio-economic and scientific implications. The HIV-1 protease enzyme is a prime therapeutic target that has been exploited in an effort to reduce morbidity and mortality. However problems arise from drug toxicity and drug-resistant mutations of the protease which is a motivation for research for new, safer and effective therapies. Evidence exists to show that there are significant genomic differences in Subtype B and C that have a negative effect on the intrinsic binding of inhibitors. It is imperative to look at all perspectives from epidemiological, molecular to the pharmacological ones so as to achieve rational design of therapeutic agents. This study involved the use of in silico structural analysis of the effects of mutations in the active site. The data was provided by the National Institute of Communicable Diseases consisting of HIV-1 Subtype C protease sequences of 29 infants exhibiting drug-resistance to ritonavir and lopinavir. The major active site mutations causing drug resistance identified in this study were M46I, I54V and V82A using the Stanford HIV database tool. Homology modeling without extra restraints produced models with improved quality in comparison to those with restraints. MetaMQAPII results differed when models were visualized as dimers giving erroneous modeled regions in comparison to monomers. A broader study with a larger dataset of HIV-1 subtype C protease sequences is required to increase statistical confidence and in order to identify the pattern of drug resistant mutations. Homology modeling without extra restraints is preferred for calculating homology models for the HIV-1 subtype C. Further investigations needs to be done to ascertain the accuracy of validation results for dimers from MetaMQAPII as it is designed for evaluation of monomers.

Item Type:Thesis (Masters)
Uncontrolled Keywords:HIV/AIDS, HIV-1 protease enzyme, Morbidity, Mortality, Drug toxicity, Drug-resistant mutations, Inhibitors, Therapeutic agents, Ritonavir, Lopinavir, Homology modeling
Subjects:Q Science > QD Chemistry > QD241 Organic chemistry > QD415 Biochemistry
R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
Divisions:Faculty > Faculty of Science > Biochemistry, Microbiology & Biotechnology
Supervisors:Lobb, Kevin and Bishop, Özlem Tastan
ID Code:3118
Deposited By: Philip Clarke
Deposited On:12 Jul 2012 05:55
Last Modified:12 Jul 2012 05:55
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