Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks.
A major challenge in drug discovery is to distinguish the molecular targets of a bioactive compound from the hundreds to thousands of additional gene products that respond indirectly to changes in the activity of the targets. Here, we present an integrated computational-experimental approach for computing the likelihood that gene products and associated pathways are targets of a compound. This is achieved by filtering the mRNA expression profile of compound-exposed cells using a reverse-engineered model of the cell's gene regulatory network. We apply the method to a set of 515 whole-genome yeast expression profiles resulting from a variety of treatments (compounds, knockouts and induced expression), and correctly enrich for the known targets and associated pathways in the majority of compounds examined. We demonstrate our approach with PTSB, a growth inhibitory compound with a previously unknown mode of action, by predicting and validating thioredoxin and thioredoxin reductase as its target.
di Bernardo
Diego
D
Telethon Institute for Genetics and Medicine, Naples, Italy.
Thompson
Michael J
MJ
Gardner
Timothy S
TS
Chobot
Sarah E
SE
Eastwood
Erin L
EL
Wojtovich
Andrew P
AP
Elliott
Sean J
SJ
Schaus
Scott E
SE
Collins
James J
JJ
D000465:Algorithms; D001185:Artificial Intelligence; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D015233:Models, Statistical; D015202:Protein Engineering / Q000379:methods*; D025941:Protein Interaction Mapping / Q000379:methods; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism
D029701:Saccharomyces cerevisiae Proteins; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase