Understanding the Role of H‑Bonds in the Stability of Molecular Glue-Induced Ternary Complexes
Patricia Blanco-Gabella, Varbina Ivanova, Álvaro Serrano-Morrás, Julian E. Fuchs, Jordi Juárez-Jiménez
TL;DR
This paper explores how hydrogen bonds help stabilize protein complexes formed by molecular glues, offering insights for drug development.
Contribution
The study reveals that hydrogen bond robustness is a reproducible mechanism for molecular glue action across diverse compounds.
Findings
Hydrogen bond robustness correlates with stability in molecular glue-induced complexes.
The mechanism applies to chemically diverse molecular glues like IMiDs and Fusicoccin A.
Findings suggest new computational methods for designing molecular glues.
Abstract
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…
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Taxonomy
TopicsProtein Degradation and Inhibitors · Click Chemistry and Applications · Biochemical and Structural Characterization