2024/07/29 by Andreas Beier, Gerald Platzer, Theresa Höfurthner +7 · 1 voice
Biochemistry, Genetics and Molecular Biology · Materials Science · #Protein Structure and Dynamics #Chemical Synthesis and Analysis #Enzyme Structure and Function
paper · doi:10.1021/acs.jmedchem.4c01128
openalex publication_date 2024/07/29 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/22
Fragment-based drug design is heavily dependent on the optimization of initial low-affinity binders. Herein we introduce an approach that uses selective labeling of methyl groups in leucine and isoleucine side chains to directly probe methyl-π contacts, one of the most prominent forms of interaction between proteins and small molecules. Using simple NMR chemical shift perturbation experiments with selected BRD4-BD1 binders, we find good agreement with a commonly used model of the ring-current effect as well as the overall interaction geometries extracted from the Protein Data Bank. By combining both interaction geometries and chemical shift calculations as fit quality criteria, we can position dummy aromatic rings into an AlphaFold model of the protein of interest. The proposed method can therefore provide medicinal chemists with important information about binding geometries of small molecules in fast and iterative matter, even in the absence of high-resolution experimental structures.