Systematic Identification of Pharmacological Targets from Small-Molecule Phenotypic Screens. Issue 10 (20th October 2016)

• Record Type: Journal Article
• Authors: Liu, Xueping; Baarsma, Hoeke Abele; Thiam, Chung Hwee; Montrone, Corinna; Brauner, Barbara; Fobo, Gisela; Heier, Julia-Sophie; Duscha, Sven; Königshoff, Melanie; Angeli, Veronique; Ruepp, Andreas; Campillos, Monica
• Is Part Of: Cell chemical biology. Volume 23:Issue 10(2016)
• Page Start: 1302
• Page End: 1313
• Publication Date: 2016-10-20
• Subjects: high-throughput chemical screens -- target de-convolution -- target prediction -- drug target-phenotype relations; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.08.011
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: DePick is a novel target de-convolution tool for chemical phenotypic screens DePick applied to 8 screens revealed 59 known and novel drug target-phenotype links DePick is publicly available athttp://mips.helmholtz-muenchen.de/Depick/ Abstract : Liu et al. present DePick, a novel target de-convolution approach to determine targets specifically linked to chemical phenotypic screens and illustrate that the application of DePick to public screens can expand the pharmacologically targetable molecular repertoire behind phenotypes with high efficiency.