Discovery of molecular glues is frequently perceived as serendipitous. Drawing on 12 fragment-based molecular glue screening campaigns across diverse protein pairs, we highlight here ten practical lessons that consistently influenced screening outcomes.  In Part 1 and Part 2 of the series we have shown that intrinsic affinity between the protein matter and that cooperativity is key in finding moleucular glues. We have shown that molecular glues are actually way more common than expected, provided that the screening assays are well set up. In this Part…

Discovery of molecular glues is frequently perceived as serendipitous. Drawing on 12 fragment-based molecular glue screening campaigns across diverse protein pairs, we highlight ten practical lessons that consistently influenced screening outcomes.  In Part 1, we explored how intrinsic protein-protein affinity and thermodynamic modelling can help establish sensitive molecular glue screens. In Part 2, we turn to practical lessons from our screening campaigns, covering how to select suitable E3 ligases, identify cooperative hits, distinguish genuine glue…

Discovery of molecular glues is frequently perceived as serendipitous. Drawing on 12 fragment-based molecular glue screening campaigns across diverse protein pairs, we discuss nine practical lessons that consistently influenced screening outcomes. These include the role of intrinsic PPI affinity, cooperativity, quantitative characterization, hit triage and assay design. While molecular glue discovery remains challenging, several principles can help to improve the probability of discovering cooperative compounds.
Molecular glues have emerged as an…