title: Novel anti-plasmodial hits identified by virtual screening of the ZINC database.
abstract: Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 μM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 μM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
authors.forename: Grace
authors.initials: G
authors.lastname: Mugumbate
authors.forename: Ana S
authors.initials: AS
authors.lastname: Newton
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D016208:Databases, Factual; D018432:Drug Resistance, Multiple / Q000235:genetics; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000235:genetics* / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011480:Protease Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D003546:Cysteine Endopeptidases; C099607:falcipain