Precise target identification for small molecules is an important and essential step in drug development. Despite its importance, there are very few unbiased, proteome-wide approaches aimed at identifying binding partners for small molecules. In addition, failure to identify unintended binding interactions can cause unexpected toxicity. Early and comprehensive identification of bound proteins will allow drug development programs to design medicinal chemistry efforts targeted at avoiding toxicity due to off-target effects.
The Woo lab has designed an innovative platform technology, called SIM-PAL (for small molecule interactome mapping by photo-affinity labeling) to precisely map regions within proteins that bind small molecules. Using a combination of chemical tagging, enrichment, mass spectrometry and informatics, SIM-PAL can provide a high resolution (peptide-level) view of the small molecule interactome. Since it can be performed in cellulo, the interactions are biologically relevant and context-dependent variations can be identified. Proof of concept experiments have been completed using NSAID’s and the results were recapitulated using classical methods of target validation, such as temperature shift assays. Due to its scalabilty and versatility, SIM-PAL is poised to transform an important and essential step in the drug discovery process.