Derivatives of 3‑Amino-2-methylpyridine as BAZ2B Bromodomain Ligands: In Silico Discovery and in Crystallo Validation

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.