title: Finding Inspiration in the Protein Data Bank to Chemically Antagonize Readers of the Histone Code.
abstract: Members of the Royal family of proteins are readers of the histone code that contain aromatic cages capable of recognizing specific sequences and lysine methylation states on histone tails. These binding modules play a key role in epigenetic signalling, and are part of a larger group of epigenetic targets that are becoming increasingly attractive for drug discovery. In the current study, pharmacophore representations of the aromatic cages forming the methyl-lysine (Me-Lys) recognition site were used to search the Protein Data Bank (PDB) for ligand binding pockets possessing similar chemical and geometrical features in unrelated proteins. The small molecules bound to these sites were then extracted from the PDB, and clustered based on fragments binding to the aromatic cages. The compounds collected are numerous and structurally diverse, but point to a limited set of preferred chemotypes; these include quaternary ammonium, sulfonium, and primary, secondary and tertiary amine moieties, as well as aromatic, aliphatic or orthogonal rings, and bicyclic systems. The chemical tool-kit identified can be used to design antagonists of the Royal family and related proteins.
authors.affiliation: Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, 7thfloor, 101 College Street, Toronto, Ontario, Canada, M5G 1L7 fax: 416-946-0880.
authors.forename: Valérie
authors.initials: V
authors.lastname: Campagna-Slater
authors.affiliation: Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, 7thfloor, 101 College Street, Toronto, Ontario, Canada, M5G 1L7 fax: 416-946-0880. matthieu.schapira@utoronto.ca.|Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8. matthieu.schapira@utoronto.ca.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
keywords: Drug design; Protein Data Bank; Protein-ligand interactions; Royal family; Virtual screening