Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders.

ABSTRACT: The Nrf2 transcription factor is a master regulator of the cellular response to oxidative stress, and Keap1 is its primary negative regulator. Activating Nrf2 by inhibiting the Nrf2-Keap1 protein-protein interaction has shown promise for treating cancer and inflammatory diseases. A loop derived from Nrf2 has been shown to inhibit Keap1 selectively, especially when cyclized, but there are no reliable design methods for predicting an optimal macrocyclization strategy. In this work, we employed all-atom, explicit-solvent molecular dynamics simulations with enhanced sampling methods to predict the relative degree of preorganization for a series of peptides cyclized with a set of bis-thioether "staples". We then correlated these predictions to experimentally measured binding affinities for Keap

SUBMITTER: Fonseca Lopez F 

PROVIDER: S-EPMC10807374 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature