ArticleJournal of medicinal chemistry2022
Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- Generation of membrane-permeable cyclic peptides inhibiting protein-protein interaction.Nature chemical biology · 2026Article
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- Identification and Functional Characterization of Cytoprotective Crocodile-Derived Peptides against Oxidatively Stressed Human Keratinocytes.ACS omega · 2026Article
- Serum Amino Acid and Fatty Acid Metabolites as Predictors of Sleep Disorders in Children: A Risk Prediction Model.Biomedicines · 2026Article
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- Rational Design of PCR12mod6, a Cathelicidin-HR-Derived Peptide with Enhanced Dual-Action Antimicrobial and Antioxidant Activity.ACS omega · 2025Article
- Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.Redox biology · 2025Review
- Virtual fragment screening for DNA repair inhibitors in vast chemical space.Nature communications · 2025Article
- A membrane permeability database for nonpeptidic macrocycles.Scientific data · 2025Article
- Target fishing: from "needle in haystack" to "precise guidance"--new technology, new strategy and new opportunity.Frontiers in pharmacology · 2025Review
- Discovery of a Series of Macrocycles as Potent Inhibitors ofJournal of medicinal chemistry · 2024Article
- Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders.Journal of chemical information and modeling · 2023Article
- A cell-active cyclic peptide targeting the Nrf2/Keap1 protein-protein interaction.Chemical science · 2023Article
- Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System.Molecules (Basel, Switzerland) · 2022Review
- Synergistic Effects of IMX-104 Components in Membrane Absorption: A Computational Study.ACS omega · 2022Article
- Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization.Life (Basel, Switzerland) · 2022Review
- The Role of Organosulfur Compounds as Nrf2 Activators and Their Antioxidant Effects.Antioxidants (Basel, Switzerland) · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.