TY - JOUR KW - Computer Simulation KW - Hydrogen Bonding KW - Models, Molecular KW - Crystallography, X-Ray KW - Humans KW - Structure-Activity Relationship KW - Ligands KW - Molecular Structure KW - Proteins KW - Reproducibility of Results KW - Drug Discovery KW - Dose-Response Relationship, Drug KW - Pyrimidines AU - J.-R. Marchand AU - G. Lolli AU - A. Caflisch AB -

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.

BT - Journal of Medicinal Chemistry C1 - 0219 DA - 2016 Nov 10 DO - 10.1021/acs.jmedchem.6b01258 IS - 21 J2 - J. Med. Chem. LA - eng M3 - Research Article N2 -

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.

PY - 2016 SE - 9919 SP - 9919 EP - 9927 T2 - Journal of Medicinal Chemistry TI - Derivatives of 3-amino-2-methylpyridine as BAZ2B bromodomain ligands: In silico discovery and in crystallo validation VL - 59 SN - 1520-4804 ER -