Exploring the binding mechanism of HDAC8 selective inhibitors: Lessons from the modification of Cap group

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Abnormal expression of histone deacetylase 8 (HDAC8) is linked to various cancers and parasitic diseases.
• HDAC8 is a potential therapeutic target, with inhibitor design focusing on selective targeting.
• Optimization of the Cap region in HDAC8 inhibitors is of significant research interest.

Purpose of the Study:

• To investigate how modifications in the Cap region of HDAC8 inhibitors affect their binding mechanisms and inhibitory activities.
• To elucidate the atomic-level interactions between selective HDAC8 inhibitors and the enzyme.
• To identify key residues involved in the binding of Cap-modified compounds.

Main Methods:

• Utilized computational approaches to analyze the binding mechanisms of three selected compounds (2c, 3g, 3n) with HDAC8.
• Performed atomic-level analysis to determine energy contributions of various residues.
• Identified specific subpockets and their interactions with inhibitor modifications.

Main Results:

• Significant differences in energy contributions were observed for five key residues: Y293, H167, D254, D165, and M261.
• A subpocket formed by residues Y293 and M261 interacts with the Cap groups of the inhibitors.
• These interactions modulate the energy contributions of residues within the metal-catalytic center (H167, D254, D165).

Conclusions:

• Compounds 2c, 3g, and 3n serve as effective molecular probes for understanding HDAC8 inhibitor binding.
• Residues Y293 and M261, forming a critical subpocket, are crucial for Cap group interactions.
• These findings highlight the importance of targeting the Y293-M261 subpocket in the design of novel, selective HDAC8 inhibitors.