title: Evaluation of broad spectrum protein kinase inhibitors to probe the architecture of the malarial cyclin dependent protein kinase Pfmrk.
abstract: We tested Pfmrk against several naphthalene and isoquinoline sulfonamides previously reported as protein kinase A (PKA) inhibitors. Pfmrk is a Cyclin Dependent protein Kinase (CDK) from Plasmodium falciparum, the causative parasite of the most lethal form of malaria. We find that the isoquinoline sulfonamides are potent inhibitors of Pfmrk and that substitution on the 5 position of the isoquinoline ring greatly influences the degree of potency. Molecular modeling studies suggest that the nitrogen atom in the isoquinoline ring plays a key role in ligand-receptor interactions. Structural analysis suggests that even subtle differences in amino acid composition within the active sites are responsible for conferring specificity of these inhibitors for Pfmrk over PKA.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Woodard
authors.forename: Susan M
authors.initials: SM
authors.lastname: Keenan
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Geyer
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D008288:Malaria / Q000188:drug therapy*; D008968:Molecular Conformation; D009281:Naphthalenes / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D009281:Naphthalenes; D013449:Sulfonamides; C031721:naphthalene; D017868:Cyclic AMP-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases