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Probing Protein-Ligand Methyl-π Interaction Geometries through Chemical Shift Measurements of Selectively Labeled Methyl Groups. | LitMetric

Probing Protein-Ligand Methyl-π Interaction Geometries through Chemical Shift Measurements of Selectively Labeled Methyl Groups.

J Med Chem

Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, Max Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.

Published: August 2024

AI Article Synopsis

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320577PMC
http://dx.doi.org/10.1021/acs.jmedchem.4c01128DOI Listing

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