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dc.contributor.authorTorres, F.
dc.contributor.authorWalser, R.
dc.contributor.authorKaderli, J.
dc.contributor.authorRossi, E.
dc.contributor.authorBobby, R.
dc.contributor.authorPacker, M. J.
dc.contributor.authorSarda, S.
dc.contributor.authorWalker, G.
dc.contributor.authorHitchin, James R
dc.contributor.authorMilbradt, A. G.
dc.contributor.authorOrts, J.
dc.date.accessioned2022-04-28T13:57:45Z
dc.date.available2022-04-28T13:57:45Z
dc.date.issued2022en
dc.identifier.citationTorres 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.en
dc.identifier.pmid35357834en
dc.identifier.doi10.1021/acs.jmedchem.1c01703en
dc.identifier.urihttp://hdl.handle.net/10541/625172
dc.description.abstractStructure-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.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1021/acs.jmedchem.1c01703en
dc.titleNMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24en
dc.typeArticleen
dc.identifier.journalJ Med Chemen
dc.description.noteen]
refterms.dateFOA2022-06-28T11:06:12Z


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