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

Francesco Bosica, Sebastian A. Andrei, João Filipe Neves, Peter Brandt, Anders Gunnarsson, Isabelle Landrieu, Christian Ottmann, Gavin O'Mahony (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 studies 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 Mg2+ 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.

Original languageEnglish
Pages (from-to)7131-7139
Number of pages9
JournalChemistry - A European Journal
Volume26
Issue number31
Early online date7 Apr 2020
DOIs
Publication statusPublished - 2 Jun 2020

Keywords

  • chelates
  • drug design
  • medicinal chemistry
  • PAINS
  • protein–protein interaction stabilization

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