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    NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24

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    Authors
    Torres, F.
    Walser, R.
    Kaderli, J.
    Rossi, E.
    Bobby, R.
    Packer, M. J.
    Sarda, S.
    Walker, G.
    Hitchin, James R
    Milbradt, A. G.
    Orts, J.
    Show allShow less
    Issue Date
    2022
    
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    Abstract
    Structure-based drug discovery (SBDD) largely relies on structural information from X-ray crystallography because traditional NMR structure calculation methods are too time consuming to be aligned with typical drug discovery timelines. The recently developed NMR molecular replacement (NMR2) method dramatically reduces the time needed to generate ligand–protein complex structures using published structures (apo or holo) of the target protein and treating all observed NOEs as ambiguous restraints, bypassing the laborious process of obtaining sequence-specific resonance assignments for the protein target. We apply this method to two therapeutic targets, the bromodomain of TRIM24 and the second bromodomain of BRD4. We show that the NMR2 methodology can guide SBDD by rationalizing the observed SAR. We also demonstrate that new types of restraints and selective methyl labeling have the potential to dramatically reduce “time to structure” and extend the method to targets beyond the reach of traditional NMR structure elucidation.
    Citation
    Torres F, Walser R, Kaderli J, Rossi E, Bobby R, Packer MJ, et al. NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24. J Med Chem. 2022;65(7):5565-74.
    Journal
    J Med Chem
    URI
    http://hdl.handle.net/10541/625172
    DOI
    10.1021/acs.jmedchem.1c01703
    PubMed ID
    35357834
    Additional Links
    https://dx.doi.org/10.1021/acs.jmedchem.1c01703
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1021/acs.jmedchem.1c01703
    Scopus Count
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    All Paterson Institute for Cancer Research

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