title: Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks.
abstract: 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.
authors.affiliation: Telethon Institute for Genetics and Medicine, Naples, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: di Bernardo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thompson
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Gardner
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Chobot
authors.forename: Erin L
authors.initials: EL
authors.lastname: Eastwood
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Wojtovich
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Elliott
authors.forename: Scott E
authors.initials: SE
authors.lastname: Schaus
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
mesh_terms: 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
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase