title: Identification and characterization of novel small molecules as potent inhibitors of the plasmodial calcium-dependent protein kinase 1.
abstract: Malaria remains a major killer in many parts of the world. Recently, there has been an increase in the role of public-private partnerships inciting academic and industrial scientists to merge their expertise in drug-target validation and in the early stage of drug discovery to identify potential new medicines. There is a need to identify and characterize new molecules showing high efficacy, low toxicity with low propensity to induce resistance in the parasite. In this context, we have studied the structural requirements of the inhibition of PfCDPK1. This is a calcium-dependent protein kinase expressed in Plasmodium falciparum, which has been genetically confirmed as essential for survival. A primary screening assay has been developed. A total of 54000 compounds were tested, yielding two distinct chemical series of nanomolar small molecule inhibitors. The most potent members of each series were further characterized through enzymatic and biophysical analyses. Dissociation rates of the inhibitor-kinase complexes were shown to be key parameters to differentiate both series. Finally, a homology-based model of the kinase core domain has been built which allows rational design of the next generation of inhibitors.
authors.affiliation: Geneva Research Center, Merck-Serono SA, 9, chemin des Mines, Case postale 54CH-1211 Geneve 20, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lemercier
authors.forename: Amaury
authors.initials: A
authors.lastname: Fernandez-Montalvan
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Shaw
authors.forename: Dominik
authors.initials: D
authors.lastname: Kugelstadt
authors.forename: Joerg
authors.initials: J
authors.lastname: Bomke
authors.forename: Mathias
authors.initials: M
authors.lastname: Domostoj
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Schwarz
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheer
authors.forename: Barbara
authors.initials: B
authors.lastname: Kappes
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
mesh_terms: D000818:Animals; D049449:Luminescence; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000302:isolation & purification / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011494:Protein Kinases; C531238:calcium-dependent protein kinase-1, Plasmodium falciparum