title: Transcriptional response networks for elucidating mechanisms of action of multitargeted agents.
abstract: Drug discovery is moving away from the single target-based approach towards harnessing the potential of polypharmacological agents that modulate the activity of multiple nodes in the complex networks of deregulations underlying disease phenotypes. Computational network pharmacology methods that use systems-level drug-response phenotypes, such as those originating from genome-wide transcriptomic profiles, have proved particularly effective for elucidating the mechanisms of action of multitargeted compounds. Here, we show, via the case study of the natural product pinosylvin, how the combination of two complementary network-based methods can provide novel, unexpected mechanistic insights. This case study also illustrates that elucidating the mechanism of action of multitargeted natural products through transcriptional response-based approaches is a challenging endeavor, often requiring multiple computational-experimental iterations.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum Helsinki 2U, Tukholmankatu 8, University of Helsinki, Helsinki 00014, Finland. Electronic address: milla.kibble@helsinki.fi.
authors.forename: Milla
authors.initials: M
authors.lastname: Kibble
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum Helsinki 2U, Tukholmankatu 8, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Suleiman A
authors.initials: SA
authors.lastname: Khan
authors.affiliation: Institute of Biomedicine, Turku Center for Disease Modeling & Functional Foods Forum, University of Turku, Turku 20014, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Saarinen
authors.affiliation: European Molecular Biology Laboratory - European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.affiliation: European Molecular Biology Laboratory - European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK; Joint Research Centre for Computational Biomedicine (JRC-COMBINE) - RWTH Aachen University, Faculty of Medicine, D-52074 Aachen, Germany.
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.affiliation: Institute of Biomedicine, Turku Center for Disease Modeling & Functional Foods Forum, University of Turku, Turku 20014, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Mäkelä
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Biomedicum Helsinki 2U, Tukholmankatu 8, University of Helsinki, Helsinki 00014, Finland; Department of Mathematics and Statistics, Quantum, University of Turku, Turku 20014, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
mesh_terms: D000818:Animals; D019295:Computational Biology; D055808:Drug Discovery; D053263:Gene Regulatory Networks; D006801:Humans