New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource.
Using whole-cell phenotypic assays, the GlaxoSmithKline high-throughput screening (HTS) diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non-specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties. The hypothetical biological target space covered by these diversity sets was investigated through bioinformatics methodologies. Consequently, three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host-pathogen targets. This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. The compound sets are provided as an open resource for future lead discovery programs, and to address important research questions.
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Imanol
I
Peña
Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
M
M
Pilar Manzano
Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Juan
J
Cantizani
Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Albane
A
Kessler
Department of Microbiology, Division of Parasitology, New York University School of Medicine, New York, NY, USA.
Julio
J
Alonso-Padilla
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Ana I
AI
Bardera
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Emilio
E
Alvarez
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Gonzalo
G
Colmenarejo
Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Ignacio
I
Cotillo
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Irene
I
Roquero
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Francisco
F
de Dios-Anton
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Vanessa
V
Barroso
Department of Microbiology, Division of Parasitology, New York University School of Medicine, New York, NY, USA.
Ana
A
Rodriguez
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, UK.
David W
DW
Gray
Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain.
Miguel
M
Navarro
Computational Biology, Quantitative Sciences, GlaxoSmithKline, Collegeville, PA, USA.
Vinod
V
Kumar
Computational Biology, Quantitative Sciences, GlaxoSmithKline, Medicines Research Center, Stevenage, Hertfordshire, UK.
Alexander
A
Sherstnev
Chemical Sciences, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, NC, USA.
David H
DH
Drewry
Computational Biology, Quantitative Sciences, GlaxoSmithKline, Collegeville, PA, USA.
James R
JR
Brown
Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
Jose M
JM
Fiandor
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
J
J
Julio Martin
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D018503:Genome, Protozoan; D057166:High-Throughput Screening Assays; D006801:Humans; D016830:Kinetoplastida / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D021261:Parasitic Sensitivity Tests / Q000379:methods*; D010802:Phylogeny; D054852:Small Molecule Libraries
D000981:Antiprotozoal Agents; D054852:Small Molecule Libraries