# GlueFinder: A Data-Driven Framework for the Rational Discovery of Molecular Glues

## TL;DR

GlueFinder is a new computational tool that helps discover molecular glues by identifying suitable binding sites on proteins, enabling the design of targeted protein degraders.

## Contribution

GlueFinder introduces a systematic, data-driven platform for identifying ligandable sites for molecular glue discovery, independent of legacy scaffolds or specific ligases.

## Key findings

- GlueFinder predicted candidate glues recruiting 24, 111, and 148 distinct E3 ligases to EGFR, HER2, and KRAS, respectively.
- The tool successfully promotes non-native EGFR complexes with diverse proteins, suggesting potential for novel ternary assemblies.
- Validation on benchmark structures confirms GlueFinder's effectiveness in identifying glue-mediated complex formation sites.

## Abstract

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.