Compound prioritization methods increase rates of chemical probe discovery in model organisms.
Preselection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in Saccharomyces cerevisiae and identified ~7500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. These data were used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes, we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7500 growth-inhibitory molecules have been made commercially available and the computational model and filter used are provided.
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
Iain M
IM
Wallace
Malene L
ML
Urbanus
Genna M
GM
Luciani
Andrew R
AR
Burns
Mitchell K L
MK
Han
Hao
H
Wang
Kriti
K
Arora
Lawrence E
LE
Heisler
Michael
M
Proctor
Robert P
RP
St Onge
Terry
T
Roemer
Peter J
PJ
Roy
Carolyn L
CL
Cummins
Gary D
GD
Bader
Corey
C
Nislow
Guri
G
Giaever
D001412:Bacillus subtilis / Q000187:drug effects / Q000254:growth & development; D001499:Bayes Theorem; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D010641:Phenotype; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000254:growth & development* / Q000378:metabolism*; D054852:Small Molecule Libraries; D013230:Stearoyl-CoA Desaturase
D001572:Benzofurans; C571079:ERG7.153; D004791:Enzyme Inhibitors; D010879:Piperazines; D054852:Small Molecule Libraries; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase; D019751:Intramolecular Transferases; C021924:lanosterol synthase