Chemoproteomics, A Broad Avenue to Target Deconvolution

Abstract

As a vital project of forward chemical genetic research, target deconvolution aims to identify the molecular targets of an active hit compound. Chemoproteomics, either with chemical probe‐facilitated target enrichment or probe‐free, provides a straightforward and effective approach to profile the target landscape and unravel the mechanisms of action. Canonical methods rely on chemical probes to enable target engagement, enrichment, and identification, whereas click chemistry and photoaffinity labeling techniques improve the efficiency, sensitivity, and spatial accuracy of target recognition. In comparison, recently developed probe‐free methods detect protein‐ligand interactions without the need to modify the ligand molecule. This review provides a comprehensive overview of different approaches and recent advancements for target identification and highlights the significance of chemoproteomics in investigating biological processes and advancing drug discovery processes.

Hunting for the Intermolecular Diels–Alderase

“…Cravatt and co-workers have also successfully applied this approach to the chemical proteomic profiling of human methyltransferases using substrate-based probes . Our research group also has a long-standing interest in using a chemoproteomic approach to explore the cellular targets of bioactive small molecules, which inspired the application of a biosynthetic intermediate probe (BIP) in identifying missing biosynthesis enzymes of plant natural products . Since Diels–Alderases typically share no characteristic sequence or domain with known enzymes, candidate proteins identified from the BIP-based target identification inevitably include false positive candidates that cannot be ruled out based on their predicted functions.…”