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

Author(s)

Felix Torres, Reto Walser, Janina Kaderli, Emanuele Rossi, Romel Bobby, Martin J. Packer, Sunil Sarda, Graeme Walker, James R. Hitchin, Alexander G. Milbradt, Julien Orts

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 NMR²methodology 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.

Organisation(s)

Department of Pharmaceutical Sciences

External organisation(s)

Eidgenössische Technische Hochschule Zürich, AstraZeneca, Cancer Research UK

Journal

Journal of Medicinal Chemistry

Volume

65

Pages

5565-5574

No. of pages

10

ISSN

0022-2623

DOI

https://doi.org/10.1021/acs.jmedchem.1c01703

Publication date

04-2022

Peer reviewed

Yes

Austrian Fields of Science 2012

106002 Biochemistry, 106006 Biophysics

ASJC Scopus subject areas

Molecular Medicine, Drug Discovery

Portal url

https://ucris.univie.ac.at/portal/en/publications/nmr-molecular-replacement-provides-new-insights-into-binding-modes-to-bromodomains-of-brd4-and-trim24(82218481-5b0f-4a52-a0a2-206f808e2ac8).html