2. Academic Validation
  3. Systematic Variation of Both the Aromatic Cage and Dialkyllysine via GCE-SAR Reveal Mechanistic Insights in CBX5 Reader Protein Binding

Systematic Variation of Both the Aromatic Cage and Dialkyllysine via GCE-SAR Reveal Mechanistic Insights in CBX5 Reader Protein Binding

  • J Med Chem. 2022 Feb 10;65(3):2646-2655. doi: 10.1021/acs.jmedchem.1c02049.
Kelsey M Kean 1,  Stefanie A Baril 1,  Kelsey N Lamb 2,  Sarah N Dishman 2,  Joseph W Treacy 3,  Kendall N Houk 3,  Eric M Brustad 1,  Lindsey I James 2,  Marcey L Waters 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of North Carolina at Chapel Hill, CB 3290, Chapel Hill, North Carolina 27599 United States.
  • 2 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 United States.
  • 3 Department of Chemistry and Biochemistry, University of California, Box 951569, Los Angeles, California 90095 United States.
PMID: 35014255 DOI: 10.1021/acs.jmedchem.1c02049
Abstract

Development of inhibitors for histone methyllysine reader proteins is an active area of research due to the importance of reader protein-methyllysine interactions in transcriptional regulation and disease. Optimized peptide-based chemical probes targeting methyllysine readers favor larger alkyllysine residues in place of methyllysine. However, the mechanism by which these larger substituents drive tighter binding is not well understood. This study describes the development of a two-pronged approach combining genetic code expansion (GCE) and structure-activity relationships (SAR) through systematic variation of both the aromatic binding pocket in the protein and the alkyllysine residues in the peptide to probe inhibitor recognition in the CBX5 chromodomain. We demonstrate a novel change in driving force for larger alkyllysines, which weaken cation-π interactions but increases dispersion forces, resulting in tighter binding. This GCE-SAR approach establishes discrete energetic contributions to binding from both ligand and protein, providing a powerful tool to gain mechanistic understanding of SAR trends.

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