Welcome to the DeepCoverMOA!

Defining the full cellular response to pharmacological agents is critical for understanding the mechanism of action (MOA) of small molecule perturbagens. Here we developed a 96-well plate-based high-throughput screening infrastructure for quantitative proteomics and applied it to screen in duplicate 875 drugs and tool compounds in a human cancer cell line with near-comprehensive proteome coverage. By examining the 24-hr proteome changes, we gained insights into ligand-induced changes in protein expression and generated rules by which compounds regulate their protein targets, finding putative DHFR and TNKS inhibitors. We leveraged protein-protein and compound-compound correlation networks to uncover previously unknown MOAs for several compounds, including the adrenergic receptor antagonist JP-1302, which we show disrupts the FACT complex and degrades histone H1. By defining the proteome-wide fingerprints of small molecule ligands with known protein targets, we provide a protein-level companion to RNA-expression-based MOA deconvolution pipelines. These findings highlight the power of this resource as a tool for both drug discovery and drug repurposing. By screening many compounds with overlapping targets covering a broad chemical space, we linked compound structure to MOA while highlighting clear off target polypharmacology for molecules within the library.

Instructions

Protein Centric View

Selecting a protein of interest will populate the protein map depicting the log2 fold chagne (vs DMSO) for each compound. Co-regulated proteins (Pearson r>0.65) will be displayed in the heatmap and table below the protein map

Bioplex

Selecting a protein of interest will populate the subnetwork that shows the interactors of the selected protein in Bioplex (Current) or interactions between the selected protein and its co-regulated proteins (Co-regulated).

Compound Centric View

Selecting a compound of interest will populate the structure, protein map (|log2FC|>0.15), and the protein quantification table for each protein. Correlated compounds (Pearson r >0.4) will be displayed in the panel below

Find Similar Compounds

Uploading a protein quantification table for a compound will return compounds with similar MOA.

Peptide View

Selecting a protein will populate the peptide table and heatmap.

Download RAW Data

Citations

The DeepCoverMOA web resource was built by Jiaming Li, Dylan Mitchell, and Nathanael Bulloch

For more information see the publication: Mitchell et al.XXX

Or check out the Gygi Lab Website