Derivatives of 3-amino-2-methylpyridine as BAZ2B bromodomain ligands: In silico discovery and in crystallo validation

TitleDerivatives of 3-amino-2-methylpyridine as BAZ2B bromodomain ligands: In silico discovery and in crystallo validation
Publication TypeJournal Article
Year of Publication2016
AuthorsMarchand J.-R., Lolli G., Caflisch A.
JournalJournal of Medicinal Chemistry
Volume59
Start Page9919
Issue21
Pagination9919-9927
Date Published2016 Nov 10
Type of ArticleResearch Article
ISSN1520-4804
KeywordsComputer Simulation, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Discovery, Humans, Hydrogen Bonding, Ligands, Models, Molecular, Molecular Structure, Proteins, Pyrimidines, Reproducibility of Results, Structure-Activity Relationship
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.

DOI10.1021/acs.jmedchem.6b01258
pubindex

0219

Alternate JournalJ. Med. Chem.
PubMed ID27731638
Highlight Role: 
Drug Design