title: Combined Analysis of Phenotypic and Target-Based Screening in Assay Networks.
abstract: Small-molecule screens are an integral part of drug discovery. Public domain data in PubChem alone represent more than 158 million measurements, 1.2 million molecules, and 4300 assays. We conducted a global analysis of these data, building a network of assays and connecting the assays if they shared nonpromiscuous active molecules. This network spans both phenotypic and target-based screens, recapitulates known biology, and identifies new polypharmacology. Phenotypic screens are extremely important for drug discovery, contributing to the discovery of a large proportion of new drugs. Connections between phenotypic and biochemical, target-based screens can suggest strategies for repurposing both small-molecule and biologic drugs. For example, a screen for molecules that prevent cell death from a mutated version of superoxide-dismutase is linked with ALOX15. This connection suggests a therapeutic role for ALOX15 inhibitors in amyotrophic lateral sclerosis. An interactive version of the network is available online (http://swami.wustl.edu/flow/assay_network.html).
authors.affiliation: Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA swamidass@gmail.com.
authors.forename: S Joshua
authors.initials: SJ
authors.lastname: Swamidass
authors.affiliation: Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Constantino N
authors.initials: CN
authors.lastname: Schillebeeckx
authors.affiliation: Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Matlock
authors.affiliation: Computational Biology, GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hurle
authors.affiliation: Computational Biology, GlaxoSmithKline R&D, King of Prussia, PA, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Agarwal
mesh_terms: D000465:Algorithms; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000235:genetics; D019540:Area Under Curve; D001681:Biological Assay / Q000379:methods*; D055808:Drug Discovery; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry; D015233:Models, Statistical; D009154:Mutation; D010641:Phenotype; D012372:ROC Curve
chemical_list: D016859:Lipoxygenase Inhibitors; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase
keywords: chemoinformatics; database and data management; pharmacology: ligand binding; phenotypic drug discovery; receptor binding; statistical analyses