Molecular glues drive targeted protein degradation by stabilizing ternary complexes between proteins of interest and E3 ubiquitin ligases, but their rational design has lagged due to a limited understanding of the rules for interface recognition and an overreliance on a few ligases (e.g., VHL or Cereblon). We introduce GlueFinder, a systematic, unbiased platform that leverages structural bioinformatics to mine the Protein Data Bank for ligand-binding pockets adjacent to the protein interface which are ligandable sites that can nucleate glue-mediated complex formation. After validating its performance on a benchmark of experimentally solved dimeric structures with known and predicted glues, we applied GlueFinder to three therapeutically important targets, EGFR, HER2, and KRAS, and predicted candidate glues that recruit 24, 111, and 148 distinct E3 ligases to these targets, respectively. We further demonstrate that GlueFinder can promote the formation of non-native EGFR complexes with a variety of diverse proteins, possibly enabling ternary assemblies that would not form on their own. These results establish a general, computation-guided experimental prioritization strategy for molecular glue discovery that decouples design from legacy degrader scaffolds and specific ligase dependencies, expands the usable E3 ligase repertoire, and enables rational targeting of interfacial binding pockets.
Skolnick et al. (Mon,) studied this question.