Fig. 1. The roadmap for fragment-based covalent ligand discovery. (A) State-of-the-art chemoproteomic strategies helps to systematically unveil potential ligandable sites in disease-associated targets. Cells are treated with reactive fragments (biased towards thiols (Cys), amines (lysine) and phenols (tyrosine)) and then chemoproteomics allows identification of proteins and reaction sites. (B) Fragment-based covalent ligand screening identified covalent fragment hits, which can be evolved into a more potent, selective, biocompatible and drug-like ligands by iterative elaboration and optimization. (C) Fragment-based ligand discovery pipeline holds great promise as an initial ligand-discovery approach that can be elaborated to make bivalent molecules that can recruit other enzymes including E3s for PROTACs etc.