Title page for ETD etd-03022006-151329


Document Type Master's Dissertation
Author Burger, Pieter Buys
Email pieter.burger@tuks.co.za
URN etd-03022006-151329
Document Title Functional and structural properties of an in silico model of Plasmodium falciparum spermidine synthase
Degree MSc (Biochemistry)
Department Biochemistry
Supervisor
Advisor Name Title
Prof F Joubert
Prof A I Louw Supervisor
Keywords
  • no key words available
Date 2005-05-08
Availability restricted
Abstract
Half of the world’s population live in 103 countries plagued by malaria and more than a million people die annually of this devastating disease. Between 300 and 500 million clinical cases presents itself annually in these countries. 90% of the world’s malaria occurs in sub-Saharan Africa and most infections are due to P. falciparum, the most virulent human malaria parasite. The poorest nations are most at risk and malaria is estimated to cost these already poverty stricken countries an estimated US$12 billion annually. The increase in drug resistance, especially multiple drug resistance, is of great concern and highlights the pressing need for new anti-malarials.

Rational drug design is a method where a 3D structure is used to assist in the design of new drugs. Since malaria proteins are difficult to express in high enough quantities to be crystallized, there are only a few malarial protein structures available that can be used in such studies. The use of computationally derived models provides an alternative to this limitation. In this study a computational approach was taken to gain further insight into the structure of PfSpmdSyn. The homology model of PfSpmdSyn was constructed from SpmdSyn of T. maritime and A. thaliana. The interactions between PfSpmdSyn and its two substrates, putrescine and dcAdoMet could not be obtained from docking studies and had to be derived from the substrate analogue AdoDATO. The PfSpmdSyn model was further refined by subjecting it to molecular dynamics to find the optimal interaction between the protein and substrates. The PfSpmdSyn homology models were partially validated by explaining mutational studies, which have been performed prior to the generation of the model. Additional mutational studies have been suggested to further validate the PfSpmdSyn homology model.

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