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

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2024-05, Vol.17 (5), p.620
• Main Authors: Curcio, Antonio, Rocca, Roberta, Alcaro, Stefano, Artese, Anna
• Format: Article
• Language: English
• Subjects: Amino acids; Analysis; Apoptosis; Binding sites; Cancer; Cell cycle; Cell growth; Computational biology; DNA binding proteins; drug design; Drugs; Enzymes; Genetic aspects; Genetic transcription; HDACs inhibitors; HDACs structure; Health aspects; Heart; histone deacetylases (HDACs); Histones; Localization; Methods; Molecular dynamics; molecular modeling; Musculoskeletal system; Nervous system diseases; Physiology; Protease inhibitors; Proteins; Structure; Structure-activity relationship (Pharmacology); Structure-activity relationships; Testing; Transcription factors; Yeast; Zinc
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17050620

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 methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure-activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson-Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.