Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders

Scott J. Hughes, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalReview articlepeer-review

65 Citations (Scopus)
276 Downloads (Pure)

Abstract

Molecular glues and bivalent inducers of protein degradation (also known as PROTACs) represent a fascinating new modality in pharmacotherapeutics: the potential to knockdown previously thought ‘undruggable’ targets at sub-stoichiometric concentrations in ways not possible using conventional inhibitors. Mounting evidence suggests these chemical agents, in concert with their target proteins, can be modelled as three-body binding equilibria that can exhibit significant cooperativity as a result of specific ligand-induced molecular recognition. Despite this, many existing drug design and optimization regimens still fixate on binary target engagement, in part due to limited structural data on ternary complexes. Recent crystal structures of protein complexes mediated by degrader molecules, including the first PROTAC ternary complex, underscore the importance of protein protein interactions and intramolecular contacts to the mode of action of this class of compounds. These discoveries have opened the door to a new paradigm for structure-guided drug design: borrowing surface area and molecular recognition from nature to elicit cellular signalling.
Original languageEnglish
Pages (from-to)505-516
Number of pages12
JournalEssays in Biochemistry
Volume61
Issue number5
DOIs
Publication statusPublished - 8 Nov 2017

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