The paper provides a comprehensive review of histone deacetylases (HDACs), focusing on their structural features and the application of computational methods in the discovery of HDAC inhibitors. HDACs are crucial enzymes involved in gene transcription and chromatin regulation, playing significant roles in various biological processes and diseases, including cancer, neurodegenerative disorders, and inflammatory conditions. The review categorizes HDACs into four classes (Class I, II, III, and IV) based on their structure, function, and sequence homology. It details the structural characteristics of each class, highlighting the importance of zinc ions and NAD+ in their catalytic activity. The paper also discusses the role of HDACs in epigenetic regulation, their interactions with other proteins, and the impact of mutations on their function. Computational methods, such as ligand-based approaches (scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and molecular docking) and structure-based virtual screening, have been instrumental in the design and optimization of HDAC inhibitors. These methods have improved the potency and selectivity of inhibitors, reducing non-selective toxicity. Recent advancements in molecular dynamics simulations and surface area techniques have enhanced the prediction of ligand binding affinity. The review further explores the therapeutic potential of HDAC inhibitors, particularly in cancer treatment. It highlights the development of FDA-approved HDAC inhibitors like Vorinostat, Panobinostat, Romidepsin, and Belinostat, and the ongoing research into more selective inhibitors. The paper also discusses the challenges and future directions in HDAC inhibitor development, emphasizing the need for safer and more effective inhibitors. Overall, the paper underscores the importance of understanding the structural and functional differences among HDAC isoforms to develop targeted and selective inhibitors, contributing to the advancement of HDAC-based therapies.The paper provides a comprehensive review of histone deacetylases (HDACs), focusing on their structural features and the application of computational methods in the discovery of HDAC inhibitors. HDACs are crucial enzymes involved in gene transcription and chromatin regulation, playing significant roles in various biological processes and diseases, including cancer, neurodegenerative disorders, and inflammatory conditions. The review categorizes HDACs into four classes (Class I, II, III, and IV) based on their structure, function, and sequence homology. It details the structural characteristics of each class, highlighting the importance of zinc ions and NAD+ in their catalytic activity. The paper also discusses the role of HDACs in epigenetic regulation, their interactions with other proteins, and the impact of mutations on their function. Computational methods, such as ligand-based approaches (scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and molecular docking) and structure-based virtual screening, have been instrumental in the design and optimization of HDAC inhibitors. These methods have improved the potency and selectivity of inhibitors, reducing non-selective toxicity. Recent advancements in molecular dynamics simulations and surface area techniques have enhanced the prediction of ligand binding affinity. The review further explores the therapeutic potential of HDAC inhibitors, particularly in cancer treatment. It highlights the development of FDA-approved HDAC inhibitors like Vorinostat, Panobinostat, Romidepsin, and Belinostat, and the ongoing research into more selective inhibitors. The paper also discusses the challenges and future directions in HDAC inhibitor development, emphasizing the need for safer and more effective inhibitors. Overall, the paper underscores the importance of understanding the structural and functional differences among HDAC isoforms to develop targeted and selective inhibitors, contributing to the advancement of HDAC-based therapies.