Understanding the Role of H-Bonds in the Stability of Molecular Glue-Induced Ternary Complexes

Protein-protein interaction (PPI) networks play a central role in many biological processes, and thus, the possibility of modulating them using small molecules offers several therapeutic opportunities. Molecular glues (MGs) are small molecules that bind to a PPI interface and stabilize the complex. Oftentimes, MGs show no measurable affinity for at least one of the proteins involved in the ternary complex, and the molecular bases for their action are not completely understood. We previously reported a significant correlation between protein-protein hydrogen bond robustness and the stability of the CRBN-CK1α complex induced by the antimyeloma drug lenalidomide. In this work, we demonstrate that this relationship is not unique for that system but rather represents a reproducible physicochemical phenomenon underlying the mechanism of action of chemically diverse MGs, including additional IMiDs and Fusicoccin A. Our results shed light on a vaguely understood phenomenon and pave the way for the development of new computational methods that enable the rational discovery of molecular glues.