A fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small molecule-protein interactions in human cells.
Excavating clear structure-activity relationships from these “ligandability” maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments (FFFs) differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or “enantioprobes”, we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into FFF libraries provides a robust and streamlined method to discover ligandable proteins in cells.
InstitutionThe Scripps Research Institute
ORCID For Submitting Author0000-0001-5330-3492
Declaration of Conflict of InterestThe authors declare competing financial interests. B.F.C. is a founder and advisor to Vividion Therapeutics, a biotechnology company interested in using chemical proteomic methods to develop small-molecule drugs to treat human disease. C.G.P. serves as a consultant for Vividion Therapeutics.