title: Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum.
abstract: Malaria is endemic in most developing countries, with nearly 500 million cases estimated to occur each year. The need to design a new generation of antimalarial drugs that can combat the most drug-resistant forms of the malarial parasite is well recognized. In this study, we wanted to develop inhibitors of key proteins that form the invasion machinery of the malarial parasite. A critical feature of host-cell invasion by apicomplexan parasites is the interaction between the carboxy terminal tail of myosin A (MyoA) and the myosin tail interacting protein (MTIP). Using the cocrystal structure of the Plasmodium knowlesi MTIP and the MyoA tail peptide as input to the hybrid structure-based virtual screening approach, we identified a series of small molecules as having the potential to inhibit MTIP-MyoA interactions. Of the initial 15 compounds tested, a pyrazole-urea compound inhibited P. falciparum growth with an EC(50) value of 145 nM. We screened an additional 51 compounds belonging to the same chemical class and identified 8 compounds with EC(50) values less than 400 nM. Interestingly, the compounds appeared to act at several stages of the parasite's life cycle to block growth and development. The pyrazole-urea compounds identified in this study could be effective antimalarial agents because they competitively inhibit a key protein-protein interaction between MTIP and MyoA responsible for the gliding motility and the invasive features of the malarial parasite.
authors.affiliation: Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania, USA. sandhya.kortagere@drexelmed.edu
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kortagere
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Morrisey
authors.forename: Thomas
authors.initials: T
authors.lastname: Daly
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Ejigiri
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
authors.forename: Akhil B
authors.initials: AB
authors.lastname: Vaidya
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Bergman
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008958:Models, Molecular; D024507:Nonmuscle Myosin Type IIA / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D014508:Urea / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D011720:Pyrazoles; D054852:Small Molecule Libraries; C031280:pyrazole; D014508:Urea; D024507:Nonmuscle Myosin Type IIA