title: In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen.
abstract: The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: David
authors.initials: D
authors.lastname: Plouffe
authors.forename: Achim
authors.initials: A
authors.lastname: Brinker
authors.forename: Case
authors.initials: C
authors.lastname: McNamara
authors.forename: Kerstin
authors.initials: K
authors.lastname: Henson
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Francisco
authors.initials: F
authors.lastname: Adrián
authors.forename: Jason T
authors.initials: JT
authors.lastname: Matzen
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Nam
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Arnab
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Jeff
authors.initials: J
authors.lastname: Janes
authors.forename: S Frank
authors.initials: SF
authors.lastname: Yan
authors.forename: Richard
authors.initials: R
authors.lastname: Trager
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Caldwell
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016000:Cluster Analysis; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D008958:Models, Molecular; D010271:Parasites / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry
chemical_list: D000962:Antimalarials; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase