title: Using functional signature ontology (FUSION) to identify mechanisms of action for natural products.
abstract: A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA (miRNA) libraries. With this strategy, we matched proteins and miRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected siRNAs, miRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets.
authors.affiliation: 1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Malia B
authors.initials: MB
authors.lastname: Potts
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Fisher
authors.forename: Youcai
authors.initials: Y
authors.lastname: Hu
authors.forename: Yazmin P
authors.initials: YP
authors.lastname: Carrasco
authors.forename: Gamze Betul
authors.initials: GB
authors.lastname: Bulut
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Ou
authors.forename: Mireya L
authors.initials: ML
authors.lastname: Herrera-Herrera
authors.forename: Federico
authors.initials: F
authors.lastname: Cubillos
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mendiratta
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.forename: Matan
authors.initials: M
authors.lastname: Hofree
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Lily Jun-shen
authors.initials: LJ
authors.lastname: Huang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
authors.forename: John B
authors.initials: JB
authors.lastname: MacMillan
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001419:Bacteria / Q000737:chemistry / Q000145:classification; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D007448:Invertebrates / Q000737:chemistry; D061986:MCF-7 Cells; D008386:Marine Biology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D001688:Biological Products; D035683:MicroRNAs