BRD4
April 2021
The bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extra-terminal (BET) protein family. It acts as a transcriptional regulator and plays an essential role in homeostasis. The abnormal expression and disfunction of BRD4 have been found in many cancers and inflammatory disorders, making it a promising epigenetic target.
BRD4’s two N-terminal bromodomains - BD1 and BD2 have primarily been investigated as potential targets for small-molecule drug design. These motifs are responsible for BRD4’s binding to acetylated lysine residues on histones. Such binding sites are highly conserved not only among BET proteins but also between bromodomains belonging to the same family member.
In 3decision, more than 400 structures of BRD4 are registered from the PDB database. Since BRD4 has not yet been resolved in its full-length, current structures cover BD1 or BD2 motifs. Besides many BRD4 structures having co-crystallized ligands, some of them are in apo forms.
Collection of all 379 ligands co-crystalized in BRD4 BD1 acetyl-lysine binding site and refined set of 29 ligands that interact with selected BRD4 BD1 binding site residues (Asp144 and Ile146).
Let’s assume one needs to collect all the ligands binding to BDR4 BD1: using 3decision it is a matter of just one click. Moreover, by using the 3decision “Search ligands binding to certain amino acids” feature, it is also easy to further refine the collection to keep only those ligands that interact with non-conserved binding site residues of BRD4 BD1 with respect to its 49%-similar BRD4 BD2. Here the non-conserved residues of BD1 (Asp144 and Ile146) are selected. In a matter of seconds, you get the set of all co-crystallized ligands from public resources that interact with these BD1 specific residues. This collection might serve as a good starting point for a drug design project targeting BRD4 BD1.
Reference: Tang P, Zhang J, Liu J, Chiang CM, Ouyang L. Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development. J Med Chem. 2021 Mar 11;64(5):2419-2435. doi: 10.1021/acs.jmedchem.0c01487. Epub 2021 Feb 22. PMID: 33616410. https://pubmed.ncbi.nlm.nih.gov/33616410/
Our team did a small project on ligand optimization of a PROTAC small molecule on BDR4 with 3decision. Have a look here.
Check out our webinar to learn how to easily collect datasets for SBDD projects with 3decision here.