Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction
| Autor: | Fabio Begnini, Stefan Geschwindner, Patrik Johansson, Lisa Wissler, Richard J. Lewis, Emma Danelius, Andreas Luttens, Pierre Matricon, Jens Carlsson, Stijn Lenders, Beate König, Anna Friedel, Peter Sjö, Stefan Schiesser, Jan Kihlberg |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Models
Molecular Macrocyclic Compounds NF-E2-Related Factor 2 Chemistry Medicinal Ligands CONFORMATIONS Structure-Activity Relationship Drug Discovery Animals Humans PEPTIDE Pharmacology & Pharmacy FREE-ENERGY CALCULATIONS Science & Technology Binding Sites Kelch-Like ECH-Associated Protein 1 POTENT Biochemistry and Molecular Biology Läkemedelskemi Rats DRUG DISCOVERY Molecular Docking Simulation FORCE-FIELD Hepatocytes Microsomes Liver Molecular Medicine Medicinal Chemistry Life Sciences & Biomedicine Biokemi och molekylärbiologi Signal Transduction |
| Popis: | 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. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:65 issue:4 pages:3473-3517 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|