Design Of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization

TL;DR

This study uncovers a novel chelation-controlled mechanism for stabilizing 14-3-3 protein-protein interactions, leading to the design of potent, selective, and drug-like stabilizers with potential therapeutic applications.

Contribution

It introduces a new chelation-based strategy for enhancing PPI stabilization potency, enabling the design of drug-like stabilizers for 14-3-3 proteins.

Findings

Discovery of metal ion-dependent stabilization mechanism

Design of the first potent, selective 14-3-3 PPI stabilizers

Demonstration of chelation as a medicinal chemistry strategy

Abstract

The protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such study have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg 2+ leading to the discovery of metal ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective and drug-like 14-3-3 PPI stabilizers.