Titel
NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24
Autor*in
Felix Torres
Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, Eidgenossische Technische Hochschule Zurich
Janina Kaderli
Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, Eidgenossische Technische Hochschule Zurich
... show all
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.
Stichwort
Drug DiscoveryMolecular Medicine
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Journal of Medicinal Chemistry
Band
65
Ausgabe
7
ISSN
0022-2623
Erscheinungsdatum
2022
Seitenanfang
5565
Seitenende
5574
Publication
American Chemical Society (ACS)
Erscheinungsdatum
2022
Zugänglichkeit
Rechte
Rechteangabe
© 2022 The Authors
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