Systematic Identification of Pharmacological Targets from Small-Molecule Phenotypic Screens.
Phenotypic drug discovery offers some advantages over target-based methods, mainly because it allows drug leads to be tested in systems that more closely model distinct disease states. However, a potential disadvantage is the difficulty of linking the observed phenotype to a specific cellular target. To address this problem, we developed DePick, a computational target de-convolution tool to determine targets specifically linked to small-molecule phenotypic screens. We applied DePick to eight publicly available screens and predicted 59 drug target-phenotype associations. In addition to literature-based evidence for our predictions, we provide experimental support for seven predicted associations. Interestingly, our analysis led to the discovery of a previously unrecognized connection between the Wnt signaling pathway and an aromatase, CYP19A1. These results demonstrate that the DePick approach can not only accelerate target de-convolution but also aid in discovery of new functionally relevant biological relationships.
Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany; German Center for Diabetes Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Xueping
X
Liu
Research Unit Lung Repair and Regeneration, Comprehensive Pneumology Center, Helmholtz Zentrum Munich, University Hospital Großhadern, Ludwig-Maximilians-University, 81337 Munich, Member of the German Center of Lung Research (DZL), Germany.
Hoeke Abele
HA
Baarsma
Department of Microbiology, Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
Chung Hwee
CH
Thiam
Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Corinna
C
Montrone
Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Barbara
B
Brauner
Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Gisela
G
Fobo
Technical University Munich WZW Chair of Bioinformatics, 80333 Munich, Germany.
Julia-Sophie
JS
Heier
Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Sven
S
Duscha
Research Unit Lung Repair and Regeneration, Comprehensive Pneumology Center, Helmholtz Zentrum Munich, University Hospital Großhadern, Ludwig-Maximilians-University, 81337 Munich, Member of the German Center of Lung Research (DZL), Germany.
Melanie
M
Königshoff
Department of Microbiology, Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
Veronique
V
Angeli
Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Andreas
A
Ruepp
Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany; German Center for Diabetes Research, Helmholtz Center Munich, 85764 Neuherberg, Germany. Electronic address: monica.campillos@helmholtz-muenchen.de.
Monica
M
Campillos
D000072283:A549 Cells; D000818:Animals; D002460:Cell Line; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D010641:Phenotype; D054852:Small Molecule Libraries / Q000494:pharmacology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors; D060449:Wnt Signaling Pathway / Q000187:drug effects
D054852:Small Molecule Libraries; D051153:Wnt Proteins
drug target-phenotype relations; high-throughput chemical screens; target de-convolution; target prediction