5L8T

Crystal Structure of BAZ2B bromodomain in complex with 3-amino-2-methylpyridine derivative 2

Summary for 5L8T

• Entry DOI: 10.2210/pdb5l8t/pdb
• Related: 5E9K
• Descriptor: Bromodomain adjacent to zinc finger domain protein 2B, ~{N}-[(3~{R})-1,1-bis(oxidanylidene)thian-3-yl]-2-methyl-pyridin-3-amine (3 entities in total)
• Functional Keywords: four helical bundle, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q9UIF8
• Total number of polymer chains: 1
• Total formula weight: 13771.90

Authors

Lolli, G.,Marchand, J.-R.,Caflisch, A. (deposition date: 2016-06-08, release date: 2016-10-26, Last modification date: 2024-01-10)

Primary citation

Marchand, J.R.,Lolli, G.,Caflisch, A.
Derivatives of 3-Amino-2-methylpyridine as BAZ2B Bromodomain Ligands: In Silico Discovery and in Crystallo Validation.
J. Med. Chem., 59:9919-9927, 2016

PubMed Abstract: The 3-amino-2-methylpyridine derivative 1 was identified as ligand of the BAZ2B bromodomain by automatic docking of nearly 500 compounds, selected on the basis of previous fragment hits. Hit expansion by two in silico approaches, pharmacophore search followed by docking, and substructure search resulted in five additional ligands. The predicted binding mode of the six 3-amino-2-methylpyridine derivatives was validated by protein crystallography. A small displacement of residues 1894-1899 of the ZA loop is observed for two of the six ligands. In all structures, the pyridine head is involved in a water-mediated hydrogen bond with the side chain of the conserved Tyr1901 while the 3-amino linker acts as hydrogen bond donor for the backbone carbonyl of Pro1888. Heterogeneous orientations are observed for the tail groups (i.e., the 3-amino substituents). The sulfonyl group in the tail of compounds 1 and 2 is involved in a hydrogen bond with the backbone amide of Asn1894.

PubMed: 27731638
DOI: 10.1021/acs.jmedchem.6b01258

Experimental method

X-RAY DIFFRACTION (1.85 Å)