Targeting malaria with specific CDK inhibitors.
Cyclin-dependent protein kinases (CDKs) are attractive targets for drug discovery and efforts have led to the identification of novel CDK selective inhibitors in the development of treatments for cancers, neurological disorders, and infectious diseases. More recently, they have become the focus of rational drug design programs for the development of new antimalarial agents. CDKs are valid targets as they function as essential regulators of cell growth and differentiation. To date, several CDKs have been characterized from the genome of the malaria-causing protozoan Plasmodium falciparum. Our approach employs experimental and virtual screening methodologies to identify and refine chemical inhibitors of the parasite CDK Pfmrk, a sequence homologue of human CDK7. Chemotypes of Pfmrk inhibitors include the purines, quinolinones, oxindoles, and chalcones, which have sub-micromolar IC50 values against the parasite enzyme, but not the human CDKs. Additionally, we have developed and validated a pharmacophore, based on Pfmrk inhibitors, which contains two hydrogen bond acceptor functions and two hydrophobic sites, including one aromatic ring hydrophobic site. This pharmacophore has been exploited to identify additional compounds that demonstrate significant inhibitory activity against Pfmrk. A molecular model of Pfmrk designed using the crystal structure of human CDK7 highlights key amino acid substitutions in the ATP binding pocket. Molecular modeling and docking of the active site pocket with selective inhibitors has identified possible receptor-ligand interactions that may be responsible for inhibitor specificity. Overall, the unique biochemical characteristics associated with this protein, to include distinctive active site amino acid residues and variable inhibitor profiles, distinguishes the Pfmrk drug screen as a paradigm for CDK inhibitor analysis in the parasite.
Geyer
Jeanne A
JA
Diagnostic Systems Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Ft. Detrick, MD 20910, USA. Jeanne.Geyer@det.amedd.army.mil
Prigge
Sean T
ST
Waters
Norman C
NC
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000737:chemistry*; D001665:Binding Sites; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008288:Malaria / Q000188:drug therapy* / Q000378:metabolism; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011494:Protein Kinases / Q000737:chemistry; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
D000962:Antimalarials; D004791:Enzyme Inhibitors; C484350:PfMrk protein, Plasmodium falciparum; D015800:Protozoan Proteins; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D018844:Cyclin-Dependent Kinases