Pires Gustavo Salgado, Tolomeu Heber Victor, Rodrigues Daniel Alencar, Lima Lídia Moreira, Fraga Carlos Alberto Manssour, Pinheiro Pedro de Sena Murteira
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil.
Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil.
Pharmaceuticals (Basel). 2025 Apr 16;18(4):577. doi: 10.3390/ph18040577.
Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC inhibitors (HDACis) have gained significant attention, particularly those containing zinc-binding groups (ZBGs), which interact directly with the catalytic zinc ion in the enzyme's active site. The structural diversity of ZBGs profoundly impacts the potency, selectivity, and pharmacokinetics of HDACis. While hydroxamic acids remain the most widely used ZBGs, their limitations, such as metabolic instability and off-target effects, have driven the development of alternative scaffolds, including -aminoanilides, mercaptoacetamides, alkylhydrazides, oxadiazoles, and more. This review explores the structural and mechanistic aspects of different ZBGs, their interactions with HDAC isoforms, and their influence on inhibitor selectivity. Advances in structure-based drug design have allowed the fine-tuning of HDACi pharmacophores, leading to more selective and efficacious compounds with improved drug-like properties. Understanding the nuances of ZBG interactions is essential for the rational design of next-generation HDACis, with potential applications in oncology, neuroprotection, and immunotherapy.
组蛋白去乙酰化酶（HDACs）是基因表达的关键调节因子，影响染色质重塑，并在各种生理和病理过程中发挥关键作用。HDAC活性异常与癌症、神经退行性疾病和炎症性疾病有关，使这些酶成为有吸引力的治疗靶点。HDAC抑制剂（HDACis）受到了广泛关注，特别是那些含有锌结合基团（ZBGs）的抑制剂，它们直接与酶活性位点的催化锌离子相互作用。ZBGs的结构多样性对HDACis的效力、选择性和药代动力学有深远影响。虽然异羟肟酸仍然是使用最广泛的ZBGs，但它们的局限性，如代谢不稳定性和脱靶效应，推动了替代支架的开发，包括α-氨基苯甲酰胺、巯基乙酰胺、烷基酰肼、恶二唑等。本综述探讨了不同ZBGs的结构和机制方面、它们与HDAC亚型的相互作用以及它们对抑制剂选择性的影响。基于结构的药物设计进展使得HDACi药效团能够得到微调，从而产生具有更好类药性质的更具选择性和有效性的化合物。了解ZBG相互作用的细微差别对于下一代HDACis的合理设计至关重要，其在肿瘤学、神经保护和免疫治疗方面具有潜在应用。
