Selective inhibition of Pfmrk, a Plasmodium falciparum CDK, by antimalarial 1,3-diaryl-2-propenones.
The cyclin dependent protein kinases, Pfmrk and PfPK5, most likely play an essential role in cell cycle control and differentiation in Plasmodium falciparum and are thus an attractive target for antimalarial drug development. Various 1,3-diaryl-2-propenones (chalcone derivatives) which selectivity inhibit Pfmrk in the low micromolar range (over PfPK5) are identified. Molecular modeling shows a pair of amino acid residues within the Pfmrk active site which appear to confer this selectivity. Predicted interactions between the chalcones and Pfmrk correlate well with observed potency. Pfmrk inhibition and activity against the parasite in vitro correlate weakly. Several mechanisms of action have been suggested for chalcone derivatives and our study suggests that kinase inhibition may be an additional mechanism of antimalarial activity for this class of compounds.
Geyer
Jeanne A
JA
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
Keenan
Susan M
SM
Woodard
Cassandra L
CL
Thompson
Philip A
PA
Gerena
Lucia
L
Nichols
Daniel A
DA
Gutteridge
Clare E
CE
Waters
Norman C
NC
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000962:Antimalarials; D047188:Chalcones; C484350:PfMrk protein, Plasmodium falciparum; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011494:Protein Kinases