Exploring Cocrystallized Aromatic Cage Binders to Target Histone Methylation Reader Proteins

Histone methylation
reader proteins (HMRPs) regulate gene transcription
by recognizing, at their “aromatic cage” domains, various
Lys/Arg methylation states on histone tails. Because epigenetic dysregulation
underlies a wide range of diseases, HMRPs have become attractive drug
targets. However, structure-based efforts in targeting them are still
in their infancy. Structural information from functionally unrelated
aromatic-cage-containing proteins (ACCPs) and their cocrystallized
ligands could be a good starting point. In this light, we mined the
Protein Data Bank to retrieve the structures of ACCPs in complex with
cationic peptidic/small-molecule ligands. Our analysis revealed that
the vast majority of retrieved ACCPs belong to three classes: transcription
regulators (chiefly HMRPs), signaling proteins, and hydrolases. Although
acyclic (and monocyclic) amines and quats are the typical cation-binding
functional groups found in HMRP small-molecule inhibitors, numerous
atypical cationic groups were identified in non-HMRP inhibitors, which
could serve as potential bioisosteres to methylated Lys/Arg on histone
tails. Also, as HMRPs are involved in protein–protein interactions,
they possess large binding sites, and thus, their selective inhibition
might only be achieved by large and more flexible (beyond rule of
five) ligands. Hence, the ligands of the collected dataset represent
suitable versatile templates for further elaboration into potent and
selective HMRP inhibitors.