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.

Small-Molecule Ligands of Methyl-Lysine Binding Proteins

“…6 However, experimental reports of small molecule inhibitors of methyl-lysine binding proteins, readers of the histone code, are limited. 7,8 …”

Mind the Methyl: Methyllysine Binding Proteins in Epigenetic Regulation

“…For other members of the Royal family, a varying degree of druggabilty was found among the members studied. [191] Another important factor that should be considered is the tendency of these domains to be present in multiprotein complexes, which changes the topology and thus the druggabilty of the binding site.…”

“…However, as the authors also suggest, the study recovered several substructures known to address aromatic cages, which could serve as a good starting point to design novel inhibitors. [191]…”

Drug Discovery Toward Antagonists of Methyl-Lysine Binding Proteins

“…Our strategy is to take a protein-family approach [77] toward the therapeutically unbiased discovery of high quality chemical probes for readers of methyl-lysine [78, 79]. Initial results of ligand discovery via experimental and virtual screening [43, 44, 80] have confirmed some of the anticipated challenges in terms of potency for these weakly interacting domains, but also show promise for selectivity even within related MBT domain containing proteins (Table 1 ). By taking a broad and unbiased approach to probe discovery, the chances for finding potency enhancing features in ligands is increased via testing of each ligand hypothesis versus a large number of functionally homologous, but structurally distinct binding sites (as reviewed above).…”