9FXP

Crystal structure of BRD4 BD1 with DI00626383.

Summary for 9FXP

• Entry DOI: 10.2210/pdb9fxp/pdb
• Descriptor: Bromodomain-containing protein 4, 4-methoxy-1,2-benzoxazol-3-amine (3 entities in total)
• Functional Keywords: inhibitor, bromodomain, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15263.54

Authors

Bader, G.,Reinert, D. (deposition date: 2024-07-02, release date: 2024-08-07, Last modification date: 2024-08-21)

Primary citation

Beier, A.,Platzer, G.,Hofurthner, T.,Ptaszek, A.L.,Lichtenecker, R.J.,Geist, L.,Fuchs, J.E.,McConnell, D.B.,Mayer, M.,Konrat, R.
Probing Protein-Ligand Methyl-pi Interaction Geometries through Chemical Shift Measurements of Selectively Labeled Methyl Groups.
J.Med.Chem., 67:13187-13196, 2024

PubMed 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.

PubMed: 39069741
DOI: 10.1021/acs.jmedchem.4c01128

Experimental method

X-RAY DIFFRACTION (1.88 Å)