Strategies To Design Selective Histone Deacetylase Inhibitors

This review classifies drug-design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class-specific sub-pockets: the side-pocket-, lower-pocket- and foot-pocket-targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.

Automated summary

This review classifies successful drug-design strategies used in the development of histone deacetylase (HDAC) inhibitors, particularly focusing on selective HDAC inhibitors and their structure-activity relationships. The paper discusses how optimization of various structural features, such as the zinc binding group, linker, and cap group, can influence inhibitor selectivity. Additionally, it highlights the importance of targeting class-specific sub-pockets for improved inhibitor design.