Characterization, modelling and docking studies of Plasmodium falciparum kinase PfCDPK4

Abstract

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%.