In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen.
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.
Plouffe
David
D
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Brinker
Achim
A
McNamara
Case
C
Henson
Kerstin
K
Kato
Nobutaka
N
Kuhen
Kelli
K
Nagle
Advait
A
Adrián
Francisco
F
Matzen
Jason T
JT
Anderson
Paul
P
Nam
Tae-Gyu
TG
Gray
Nathanael S
NS
Chatterjee
Arnab
A
Janes
Jeff
J
Yan
S Frank
SF
Trager
Richard
R
Caldwell
Jeremy S
JS
Schultz
Peter G
PG
Zhou
Yingyao
Y
Winzeler
Elizabeth A
EA
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
D000962:Antimalarials; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase