Functionalized Scout Fragments for Site-Specific Covalent Ligand Discovery and Optimization.

ABSTRACT: Covalent ligands are a versatile class of chemical probes and drugs that can target noncanonical sites on proteins and display differentiated pharmacodynamic properties. Chemical proteomic methods have been introduced that leverage electrophilic fragments to globally profile the covalent ligandability of nucleophilic residues, such as cysteine and lysine, in native biological systems. Further optimization of these initial ligandability events without resorting to the time-consuming process of individualized protein purification and functional assay development, however, presents a persistent technical challenge. Here, we show that broadly reactive electrophilic fragments, or "scouts", can be converted into site-specific target engagement probes for screening small molecules against a wide

SUBMITTER: Crowley VM 

PROVIDER: S-EPMC8155467 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature