The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational techniques have greatly facilitated the discovery of HDAC inhibitors that achieve the desired potency and selectivity. These techniques encompass ligand-based strategies such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships (3D-QSAR), and structure-based virtual screening (molecular docking). Additionally, advancements in molecular dynamics simulations, along with Poisson–Boltzmann/molecular mechanics generalized Born surface area (PB/MM-GBSA) methods, have enhanced the accuracy of predicting ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.