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"... The invention works with an existing lab method called photo-crosslinking. Leaving behind a clean, uniform chemical signature, the technology allowed the team to directly compare how different molecules compete for the same binding site on a protein, all in a single experiment. Because most small-molecule drugs act by binding to specific protein targets, finding precisely where these molecules bind is a major benefit for drug discovery.
As proof of concept, the team analyzed the activity of dasatinib and ascinimib, two cancer drugs that target different sites on the same protein, a type of enzyme called a kinase that, when mutated, causes leukemia.
The results coincided with known interactions for each drug and revealed previously unknown interactions. The newer drug, ascinimib, which has a more favorable safety profile and fewer side effects, showed fewer off-target kinase interactions. ...
new technology, called SEE-CITE, is giving the molecule being studied the ability to detach from its payload so that each tagged molecule leaves behind a consistent calling card. This makes possible quantitative measurements and comparisons of how strongly different molecules engage a given binding site. The team also upgraded a widely used software tool to better interpret the complex data this method generates. ..."
From the abstract:
"For chemical probe and drug discovery campaigns, the pairing of mass spectrometry-based chemoproteomics with photoaffinity labelling has emerged as a favoured approach for target discovery and mode of action assignment. However, photocrosslinked peptide-compound adducts raise analytic challenges for quantitative binding site discovery.
Here, to address these challenges, we establish the Silyl Ether Enables Chemoproteomic Interaction and Target Engagement (SEE-CITE) method. SEE-CITE incorporates a fully functionalized chemically cleavable photocrosslinking handle that enables precise site-of-labelling identification and head-to-head comparisons of relative binding site engagement by chemically diverse compounds.
To ensure high-confidence localization of labelled residues, we extended the MSFragger algorithm of the FragPipe computational platform to report localization scores customized for photoaffinity labelling and SEE-CITE data.
When applied to scout fragments and analogues of select FDA-approved kinase inhibitors, SEE-CITE delineates known drug binding sites and uncovers small-molecule binding sites that affect the protein activity of RTN4 and COX5A."
Fig. 1: Establishing the SEE-CITE interaction site mapping platform using scout SEE-CITE probes.
Fig. 3: SEE-CITE mapping of ABL1 binding sites.
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