Exploring Cocrystallized Aromatic Cage Binders to Target Histone Methylation Reader Proteins

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Histone methylation reader proteins (HMRPs) regulate gene transcription via "aromatic cage" domains binding to methylated histone Lys/Arg.
• Epigenetic dysregulation involving HMRPs is implicated in various diseases, making them attractive drug targets.
• Structure-based drug design for HMRPs is nascent, necessitating exploration of related protein structures.

Purpose of the Study:

• To identify potential drug leads for HMRP inhibition by analyzing structures of aromatic-cage-containing proteins (ACCPs).
• To explore atypical cationic ligand features in non-HMRP ACCPs as potential bioisosteres for histone methylation.
• To guide the development of selective and potent HMRP inhibitors, considering their large binding sites.

Main Methods:

• Mining the Protein Data Bank (PDB) for structures of ACCPs complexed with cationic ligands.
• Classifying retrieved ACCPs based on function (transcription regulators, signaling proteins, hydrolases).
• Analyzing functional groups and structural characteristics of bound ligands.

Main Results:

• ACCPs were categorized into transcription regulators (including HMRPs), signaling proteins, and hydrolases.
• Typical HMRP inhibitor ligands feature acyclic/monocyclic amines and quats; however, non-HMRP inhibitors revealed diverse atypical cationic groups.
• Ligands from the dataset exhibit features suitable for developing large, flexible inhibitors targeting HMRP's extensive binding sites.

Conclusions:

• Structural data from ACCPs provide valuable starting points for designing HMRP inhibitors.
• Atypical cationic moieties in non-HMRP ligands offer novel bioisosteric strategies for targeting histone methylation.
• The identified ligands serve as versatile templates for creating potent and selective HMRP inhibitors for therapeutic applications.