title: Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans.
abstract: Apicomplexan parasites cause some of the most severe human diseases, including malaria (caused by Plasmodium), toxoplasmosis, and cryptosporidiosis. Treatments are limited by the lack of effective drugs and development of resistance to available agents. By exploiting novel features of protein kinases in these parasites, it may be possible to develop new treatments. We summarize here recent advances in identifying small molecule inhibitors against a novel family of plant-like, calcium-dependent kinases that are uniquely expanded in apicomplexan parasites. Analysis of the 3D structure, activation mechanism, and sensitivity to small molecules had identified several attractive chemical scaffolds that are potent and selective inhibitors of these parasite kinases. Further optimization of these leads may yield promising new drugs for treatment of these parasitic infections.
authors.affiliation: Structural Genomics Consortium, University of Toronto, MaRS South Tower, 101 College St, Toronto, ON, M5G 1L7, Canada; Toronto General Hospital Research Institute, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
authors.affiliation: Structural Genomics Consortium, University of Toronto, MaRS South Tower, 101 College St, Toronto, ON, M5G 1L7, Canada.
authors.forename: Majida
authors.initials: M
authors.lastname: El Bakkouri
authors.affiliation: Department of Molecular Microbiology, 660 S. Euclid Ave., Washington University School of Medicine, St Louis, MO 63130, USA. Electronic address: sibley@wustl.edu.
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
mesh_terms: D016782:Apicomplexa / Q000201:enzymology*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010802:Phylogeny; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011528:Protozoan Infections / Q000188:drug therapy; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D002135:Calcium-Binding Proteins; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D017346:Protein Serine-Threonine Kinases
keywords: ATP-binding pocket; chemotherapy; gatekeeper; orthogonal inhibitors; parasites; serine-threonine protein kinases