Liganddirected

Ligand-directed is a concept in chemical biology and medicinal chemistry in which a ligand—an affinity-matured small molecule, peptide, or biomolecule that binds a target such as a receptor or protein surface—is used to guide a reactive or functional payload to that target. The central idea is to couple a binding event to a controlled chemical consequence, enabling selective modification, labeling, or delivery at the target site while minimizing effects on non-targets.

In practice, a ligand is attached to a reactive handle or reporter and sometimes to a linker that positions the payload in proximity to the intended site. Upon binding, the proximity effect facilitates a reaction—such as covalent tagging, labeling with a fluorescent or affinity tag, or transfer of a functional group—to the target or neighboring residues. Variants include ligand-directed covalent labeling, ligand-directed affinity-based labeling, and ligand-directed delivery of imaging probes or therapeutics.

Applications span targeted covalent inhibitors that modify bound targets, proximity-based proteomics and imaging, and targeted drug delivery systems. The approach aims for high selectivity and modularity, enabling customization of ligands, linkers, and payloads to suit different targets and tissues. Challenges include achieving sufficient binding affinity and residence time, avoiding off-target reactions, controlling linker length and reactivity, and ensuring cellular permeability and in vivo stability.

See also: targeted covalent inhibition; proximity labeling; ligand-based proteomics.