Computational Design of Lysine Targeting Covalent Binders Using Rosetta.

ABSTRACT: Chemical probes that form a covalent bond with their target protein have been established as a powerful tool for investigating proteins and modulating their activity, but until recently were mostly targeting cysteine residues. Covalent binders that target lysine residues are increasingly reported. Covalent binding to lysine involves challenges such as the increased pK_a of the side chain and its considerable flexibility. Here, we describe two computational methods to derivatize lysine-binding covalent small-molecules based on known noncovalent binders, approaching the design problem from two opposite directions. In a "ligand-side" approach, we scan different ligand positions to install an electrophile and dock these derivatized ligands into the target protein. In a "protei

SUBMITTER: Tivon B 

PROVIDER: S-EPMC12152945 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature