Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development.
Cyclin-dependent protein kinases (CDKs) have been attractive drug targets for the development of anticancer therapies due to their direct and crucial role in the regulation of cellular proliferation. Following this trend, CDKs have been pursued as potential drug targets for several other diseases. Structure-based drug design programmes have focused on the plasmodial CDKs to develop new candidate antimalarial compounds. This review discusses the most recent advances relating to three Plasmodium falciparum CDKs (PfPK5, PfPK6 and Pfmrk) as they are developed as antimalarial drug targets. CDKs are highly conserved, and focus must be placed upon the amino acid differences between human and plasmodial CDKs in order to develop specific inhibitors. Comparisons of the active sites of human and parasite CDKs reveal sequence and potential structural variations. Using sequence analysis, molecular modelling and in vitro drug screening, it is possible to identify and develop inhibitors that specifically target the plasmodial CDKs. These efforts are aimed at identifying new classes of CDK inhibitors that may be exploited for antimalarial drug development.
Waters
Norman C
NC
United States Army Medical Research Unit-Kenya, MRU 64109 APO, AE 09831-4109, Kenya. nwaters@nairobi.mimcom.net
Geyer
Jeanne A
JA
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000502:physiology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000502:physiology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013329:Structure-Activity Relationship; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D000962:Antimalarials; D016213:Cyclins; C484350:PfMrk protein, Plasmodium falciparum; C406811:PfPK5 protein, Plasmodium falciparum; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011494:Protein Kinases; C408698:PK6 protein, Plasmodium falciparum; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase