1887

n Suid-Afrikaanse Tydskrif vir Natuurwetenskap en Tegnologie - Beskrywing, modellering en dok-studies van Plasmodium falciparum kinase PfCDPK4 - original research

Volume 38 Number 1
  • ISSN : 0254-3486
  • E-ISSN: 2222-4173

Abstract

Met die toenemende voorkoms van weerstandige Plasmodium stamme het die beheer van malaria-voorkoms en -mortaliteit weer op die voorgrond getree. Nuwe teikens en antimalariamiddels wat effektief is teen weerstandige malaria-parasiete word dus dringend benodig. Kalsium-afhanklike proteïenkinases (calcium dependent protein kinases – CDPKs) is betrokke by die beheer van ’n aantal biologiese prosesse in die malaria-parasiet, Plasmodium falciparum, met CDPK4 die belangrikste ensiem in hierdie klas. In hierdie studie is die struktuur van PfCDPK4 gebruik as templaat vir die soeke na nuwe malariamiddels. Die PfCDPK4 modelstruktuur is deur middel van homologiemodellering gegenereer en die stereochemiese kwaliteit gevalideer. Die molekulêre modelleringbenadering deur middel van in silico sifting teen die teiken-molekuul PfCDPK4 het ’n beskeie biblioteek van 20 000 chemiese verbindings ingesluit, asook ’n aantal aktiewe natuurprodukte en kliniesgoedgekeurde kinase-inhibeerders. In silico sifting van die Biofocus biblioteek teen PfCDPK4 het 26 verbindings opgelewer; in vitro sifting het bevestig dat drie van hierdie verbindings matig aktief is teen Plasmodium falciparum NF54, met persentasie inhibisie tussen 42% en 47%.


Characterization, modelling and docking studies of Plasmodium falciparum kinase PfCDPK4: The increasing incidence of Plasmodium strains that are resistant to current frontline antimalarial 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. At the same time the need to develop antimalarial drugs that furthermore prevent disease transmission, has become an increasingly important consideration. Calcium dependent protein kinases (CDPKs) regulate a variety of biological processes in the malaria parasite Plasmodium falciparum, CDPK4 being of prime importance in Plasmodium biology. In this study the structure of PfCDPK4 was used as a template in the discovery of malaria drug leads. The model structure of PfCDPK4 was generated by homology modelling, and model validation confirmed that the model of PfCDPK4 is of stereochemical quality. The molecular modelling approach of in silico screening against the target molecule PfCDPK4 utilized a large library of chemical compounds, some natural chemical compounds, and clinically approved kinase inhibitors. In silico screening of the Biofocus library against PfCDPK4 resulted in twenty-six compounds being identified; in vitro screening confirmed that three of these compounds exhibit moderate antimalarial activity against the NF54 strain of Plasmodium falciparum, with the percentage inhibition ranging between 42% and 47%.

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/content/journal/10520/EJC-16141cca02
2019-01-01
2019-10-18

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