Department of Chemistry / MSc (Chemistry) / Due to the increasing incidence of Plasmodium strains that are resistant to current frontline antimalarial
drugs, malaria remains a global public health challenge. In recent years, the emergence
of resistance to frontline antimalarial drugs including the more recently discovered artemisinin
class drugs has become one of the greatest challenges of controlling malaria incidence and
mortality. There is, therefore, an urgent need to develop novel targets and antimalarial drugs
that are effective against drug-resistant malarial parasites. Recent studies have demonstrated
that calcium dependent protein kinases (CDPKs) regulate a variety of biological processes in
the malaria parasite Plasmodium falciparum and that CDPK4 is important for parasite
development. The gene disruption of CDPK4 in Plasmodium berghei, which results in major
defects in sexual differentiation of the parasite has highlighted the importance of CDPK4 in
Plasmodium biology and suggests that it may be used as a target for therapeutic drugs.
PfCDPK4 is expressed in the gamete/gametocyte stage, and this could make PfCDPK4 an
essential target for malaria drug discovery. The structure of PfCDPK4 was used as a template in
the discovery of malaria drug leads and in designing chemical compounds or inhibitors that will
show anti-parasitic activity against the target molecule. The model structure of PfCDPK4 was
generated through homology modelling, and model structure validation confirmed that the
model structure of PfCDPK4 is of stereochemical quality. The molecular modelling approach
of in silico screening was utilized in this research, wherein a large library of chemical
compounds, some natural chemical compounds, and clinically approved kinase inhibitors were
screened against the target molecule PfCDPK4. In silico screening of the Bio-Focus library
against PfCDPK4 resulted in twenty-six compounds being identified; in vitro single screening
at a concentration of 5 μM confirmed that three compounds exhibit moderate antimalarial
activity against the NF54 strain of Plasmodium falciparum, with the percentage inhibition
ranging between 42% and 47%.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:univen/oai:univendspace.univen.ac.za:11602/400 |
| Date | 12 February 2016 |
| Creators | Makungo, Thomas |
| Contributors | Van Ree T., Tsekoa Tsepo, Mancama Dalu |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Rights | University of Venda |
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