TY - JOUR
T1 - Combined analysis of phenotypic and target-based screening in assay networks
AU - Swamidass, S. Joshua
AU - Schillebeeckx, Constantino N.
AU - Matlock, Matthew
AU - Hurle, Mark R.
AU - Agarwal, Pankaj
N1 - Funding Information:
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. This study was funded by GlaxoSmithKline R&D.
PY - 2014/6
Y1 - 2014/6
N2 - 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).
AB - 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).
KW - Chemoinformatics
KW - Database and data management
KW - Pharmacology: ligand binding
KW - Phenotypic drug discovery
KW - Receptor binding
KW - Statistical analyses
UR - http://www.scopus.com/inward/record.url?scp=84902124342&partnerID=8YFLogxK
U2 - 10.1177/1087057114523068
DO - 10.1177/1087057114523068
M3 - Article
C2 - 24563424
AN - SCOPUS:84902124342
VL - 19
SP - 782
EP - 790
JO - Journal of Biomolecular Screening
JF - Journal of Biomolecular Screening
SN - 1087-0571
IS - 5
ER -