Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

Abstract

Epigenetic regulation of genes through posttranslational regulation of proteins is a well‐explored approach for disease treatment, particularly in cancer chemotherapy. Histone deacetylases have shown significant potential as effective drug targets in therapeutic studies aiming to restore epigenetic normality in oncology. Besides their role in modifying histones, histone deacetylases can also catalyze the deacetylation of various nonhistone proteins and participate in the regulation of multiple biological processes. This paper provides a review of the classification, structure, and functional characteristics of the four classes of human histone deacetylases. The increasing abundance of structural information on HDACs has led to the gradual elucidation of structural differences among subgroups and subtypes. This has provided a reasonable explanation for the selectivity of certain HDAC inhibitors. Currently, the US FDA has approved a total of six HDAC inhibitors for marketing, primarily for the treatment of various hematological tumors and a few solid tumors. These inhibitors all have a common pharmacodynamic moiety consisting of three parts: CAP, ZBG, and Linker. In this paper, the structure–effect relationship of HDAC inhibitors is explored by classifying the six HDAC inhibitors into three main groups: isohydroxamic acids, benzamides, and cyclic peptides, based on the type of inhibitor ZBG. However, there are still many questions that need to be answered in this field. In this paper, the structure‐functional characteristics of HDACs and the structural information of the pharmacophore model and enzyme active region of HDAC is are considered, which can help to understand the inhibition mechanism of the compounds as well as the rational design of HDACs. This paper integrates the structural‐functional characteristics of HDACs as well as the pharmacophore model of HDAC is and the structural information of the enzymatic active region, which not only contributes to the understanding of the inhibition mechanism of the compounds, but also provides a basis for the rational design of HDAC inhibitors.

Epigenetic Changes in Alzheimer’s Disease: DNA Methylation and Histone Modification

“…Class IV includes only HDAC11. Its structure resembles both Class I and II HDACs, and its functions are still being elucidated (see [105] for structural details about the four classes).…”

Unraveling the Epigenetic Tapestry: Decoding the Impact of Epigenetic Modifications in Hidradenitis Suppurativa Pathogenesis

“…By selectively modulating these epigenetic mechanisms, it may be possible to restore normal gene expression patterns and, in turn, ameliorate or even reverse the progression of diseases. As the field of epigenetics continues to advance, it provides fertile ground for innovative therapeutic interventions and a deeper understanding of the molecular underpinnings of human health and disease [26].…”

Investigating Potential Cancer Therapeutics: Insight into Histone Deacetylases (HDACs) Inhibitions

“…In humans, a total of eighteen HDAC isoforms have currently been discovered so far and categorized into four groups based on their similarity to yeast HDACs. Class I (HDAC 1–3, and 8), class II (HDAC 4–7, 9 and 10), class III (SIRT 1–7), and class IV (HDAC11) are Zn 2+ -dependent metallohydrolases belonging to class I, II, and IV, whereas NAD+-dependent Sir2-like deacetylases belong to class III [ 11 ]. Of note, HDAC1, 2, and 3 are members of the class I isoform family, which is evolutionarily conserved.…”