ArticleJournal of medicinal chemistry2024
Probing Protein-Ligand Methyl-π Interaction Geometries through Chemical Shift Measurements of Selectively Labeled Methyl Groups.
Article in Journal of medicinal chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- NMR Studies on Protein-Ligand Interactions.International journal of molecular sciences · 2026Review
- Berberine and its structural diversity: structure-activity relationships, molecular mechanisms, and drug discovery opportunities.Molecular biology reports · 2026Review
- NMR-driven structure-based drug discovery by unveiling molecular interactions.Communications chemistry · 2025Review
- UCBShift 2.0: Bridging the Gap from Backbone to Side Chain Protein Chemical Shift Prediction for Protein Structures.Journal of the American Chemical Society · 2024Article
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
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