DRUG-seq Provides Unbiased Biological Activity Readouts for Neuroscience Drug Discovery.
Jingyao Li, Daniel J Ho, Martin Henault, Chian Yang, Marilisa Neri, Robin Ge, Steffen Renner, Leandra Mansur, Alicia Lindeman, Brian Kelly, Tayfun Tumkaya, Xiaoling Ke, Gilberto Soler-Llavina, Gopi Shanker, Carsten Russ, Marc Hild, Caroline Gubser Keller, Jeremy L Jenkins, Kathleen A Worringer, Frederic D Sigoillot, Robert J Ihry
ACS chemical biology·2022
Unbiased transcriptomic RNA-seq data has provided deep insights into biological processes. However, its impact in drug discovery has been narrow given high costs and low throughput. Proof-of-concept studies with Digital RNA with pertUrbation of Genes (DRUG)-seq demonstrated the potential to address this gap. We extended the DRUG-seq platform by subjecting it to rigorous testing and by adding an open-source analysis pipeline. The results demonstrate high reproducibility and ability to resolve the mechanism(s) of action for a diverse set of compounds. Furthermore, we demonstrate how this data can be incorporated into a drug discovery project aiming to develop therapeutics for schizophrenia using human stem cell-derived neurons. We identified both an on-target activation signature, induced by a set of chemically distinct positive allosteric modulators of the -methyl-d-aspartate (NMDA) receptor, and independent off-target effects. Overall, the protocol and open-source analysis pipeline are a step toward industrializing RNA-seq for high-complexity transcriptomics studies performed at a saturating scale.