6FO5

FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR #17

Summary for 6FO5

• Entry DOI: 10.2210/pdb6fo5/pdb
• Descriptor: Bromodomain-containing protein 4, ~{N}-[[4-[[7-ethyl-2,6-bis(oxidanylidene)purin-3-yl]methyl]phenyl]methyl]-2-oxidanylidene-1,3,4,5-tetrahydro-1-benzazepine-7-sulfonamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, histone, epigenetic reader, bromodomain, brd4(bd1), dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15684.02

Authors

Raux, B.,Betzi, S. (deposition date: 2018-02-06, release date: 2018-06-20, Last modification date: 2024-01-17)

Primary citation

Hoffer, L.,Voitovich, Y.V.,Raux, B.,Carrasco, K.,Muller, C.,Fedorov, A.Y.,Derviaux, C.,Amouric, A.,Betzi, S.,Horvath, D.,Varnek, A.,Collette, Y.,Combes, S.,Roche, P.,Morelli, X.
Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach.
J. Med. Chem., 61:5719-5732, 2018

PubMed Abstract: Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chemical probes consisting of a focused-chemical-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chemical reactions carefully chosen from a list of one-step organic transformations relevant in medicinal chemistry. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compounds with improved affinity by several orders of magnitude.

PubMed: 29883107
DOI: 10.1021/acs.jmedchem.8b00653

Experimental method

X-RAY DIFFRACTION (0.95 Å)