Structural simulation and selective inhibitor discovery study for histone demethylases KDM4E/6B from a computational...

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Lysine and arginine methylation/demethylation are crucial for gene regulation and disease.
• Histone lysine methylation by KMTs and KDMs impacts cellular homeostasis, cancer, and aging.
• KDM4E and KDM6B are key lysine demethylases involved in gene regulation, inflammation, and cancer.

Purpose of the Study:

• To investigate the molecular basis for selective inhibition of KDM4E and KDM6B.
• To understand the binding interactions of KDM4E and KDM6B with their respective inhibitors, DA-24905 and GSK-J1.
• To explore potential therapeutic strategies targeting specific KDM members.

Main Methods:

• Sequence alignment
• Molecular docking
• Molecular dynamics simulations
• Free energy calculations

Main Results:

• KDM4E and KDM6B share similar binding cavities but possess distinct crucial amino acid residues.
• Diverse binding modes were observed between the proteins and their selective inhibitors.
• Specific interactions significantly influence the selective inhibition of KDM4E and KDM6B.

Conclusions:

• Despite structural similarities, KDM4E and KDM6B exhibit unique binding characteristics.
• Selective inhibition is driven by specific amino acid residues and interaction patterns.
• Targeting specific KDMs offers promising therapeutic avenues for KDM-associated diseases.