title: Identification of plasmepsin inhibitors as selective anti-malarial agents using ligand based drug design.
abstract: We describe the application of ligand based virtual screening technologies towards the discovery of novel plasmepsin (PM) inhibitors, a family of malarial parasitic aspartyl proteases. Pharmacophore queries were used to screen vendor libraries in search of active and selective compounds. The virtual hits were biologically assessed for activity and selectivity using whole cell Plasmodium falciparum parasites and on target in PM II, PM IV and the closely related human homologue, Cathepsin D assays. Here we report the virtual screening highlights, structures of the hits and their demonstrated biological activity.
authors.affiliation: Molecular Design Group, School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Paul B
authors.initials: PB
authors.lastname: McKay
authors.forename: Martin B
authors.initials: MB
authors.lastname: Peters
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carta
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Flood
authors.forename: Enda
authors.initials: E
authors.lastname: Dempsey
authors.forename: Angus
authors.initials: A
authors.lastname: Bell
authors.forename: Colin
authors.initials: C
authors.lastname: Berry
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
authors.forename: Darren
authors.initials: D
authors.lastname: Fayne
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D008024:Ligands; D057055:Aspartic Acid Proteases; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin