title: Thousands of chemical starting points for antimalarial lead identification.
abstract: Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
authors.affiliation: Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.forename: Jaume
authors.initials: J
authors.lastname: Vidal
authors.forename: Cristina
authors.initials: C
authors.lastname: de Cozar
authors.forename: Emilio
authors.initials: E
authors.lastname: Alvarez
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Lavandera
authors.forename: Dana E
authors.initials: DE
authors.lastname: Vanderwall
authors.forename: Darren V S
authors.initials: DV
authors.lastname: Green
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.forename: Samiul
authors.initials: S
authors.lastname: Hasan
authors.forename: James R
authors.initials: JR
authors.lastname: Brown
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Peishoff
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.forename: Jose F
authors.initials: JF
authors.lastname: Garcia-Bustos
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000187:drug effects; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008954:Models, Biological; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D054852:Small Molecule Libraries / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries