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

## 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.

## Key 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
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.