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Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.

ABSTRACT: The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.

SUBMITTER: Sijbesma E

PROVIDER: S-EPMC8201753 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.

Sijbesma Eline E Hallenbeck Kenneth K KK Andrei Sebastian A SA Rust Reanne R RR Adriaans Joris M C JMC Brunsveld Luc L Arkin Michelle R MR Ottmann Christian C

ACS medicinal chemistry letters 20210510 6

The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a speci ...[more]

PMID: 34136078

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