Histone deacetylases: structural determinants of inhibitor selectivity

Area of Science:

• Epigenetics and molecular biology
• Drug discovery and medicinal chemistry
• Structural biology

Background:

• Histone deacetylases (HDACs) are crucial epigenetic regulators implicated in various diseases, including cancer, neurodegeneration, inflammation, and metabolic disorders.
• While clinically effective HDAC inhibitors exist, achieving selectivity for specific HDAC isoforms remains a significant challenge.
• Selective inhibitors are needed to elucidate individual isoform functions and minimize off-target adverse effects.

Purpose of the Study:

• To provide a comprehensive review of available structural information on HDACs.
• To discuss conserved and isoform-specific structural and mechanistic features of HDACs.
• To offer structure-based recommendations for designing selective HDAC inhibitors.

Main Methods:

• Comprehensive literature review of published HDAC crystal structures.
• Analysis of conserved and isoform-specific structural elements.
• Mechanistic insights into enzyme function and inhibitor interactions.

Main Results:

• Detailed examination of structural data for various HDAC isoforms.
• Identification of distinctive structural features that influence inhibitor binding and selectivity.
• Understanding of conserved and unique active site characteristics across the HDAC family.

Conclusions:

• Structural information is key to understanding HDAC function and inhibitor selectivity.
• Targeting specific structural features can enable the rational design of isoform-selective HDAC inhibitors.
• This knowledge can advance the development of more effective and safer therapeutics for HDAC-related diseases.