5TI3

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH INHIBITOR 17503468

Summary for 5TI3

• Entry DOI: 10.2210/pdb5ti3/pdb
• Related: 5TI2 5TI4 5TI5 5TI6 5TI7
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 2,5-dibromo-N-[3-(2-oxopyrrolidin-1-yl)phenyl]benzene-1-sulfonamide, ... (4 entities in total)
• Functional Keywords: bromodomain, cap, hunk1, mcap, protein binding-inhibitor complex, mitotic chromosome associated protein, cell cycle, inhibitor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15821.82

Authors

Zhu, J.-Y.,Ember, S.W.J.,SCHONBRUNN, E. (deposition date: 2016-09-30, release date: 2017-08-09, Last modification date: 2023-10-04)

Primary citation

Allen, B.K.,Mehta, S.,Ember, S.W.J.,Zhu, J.Y.,Schonbrunn, E.,Ayad, N.G.,Schurer, S.C.
Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations.
ACS Omega, 2:4760-4771, 2017

PubMed Abstract: Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel -[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein-ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein-ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors.

PubMed: 28884163
DOI: 10.1021/acsomega.7b00553

Experimental method

X-RAY DIFFRACTION (1.703 Å)