Department of Hematology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
J Mol Recognit. 2022 Dec;35(12):e2988. doi: 10.1002/jmr.2988. Epub 2022 Aug 19.
Nowadays, significant progress has been made in the development of selective histone deacetylase 6 (HDAC6) inhibitors, exerting great potential in the treatment of various malignant tumors and neurodegenerative diseases. Previously, selective inhibitory activities of HDAC inhibitors were generally considered sensitive to the interactions between the Cap group and the binding site of HDAC6, and a large number of selective HDAC6 inhibitors have been designed and synthesized based on the strategy. However, some inhibitors without Cap group could also exhibit excellent potency and selective inhibition towards HDAC6, and in this study, BRD9757 and compound 8, as capless selective HDAC6 inhibitors, were selected as molecular probes to explore the difference of their binding interactions in HDAC1&6. Through the analysis of binding-free energies and conformational rearrangements after 1 μs molecular dynamics simulation, it could be learned that although the residues in the binding site remained highly consistent, the binding mechanisms of BRD9757 and compound 8 in HDAC1&6 were different, which will provide valuable hints for the discovery of novel selective HDAC6 inhibitors.
如今，选择性组蛋白去乙酰化酶 6（HDAC6）抑制剂的开发取得了重大进展，在治疗各种恶性肿瘤和神经退行性疾病方面具有巨大潜力。此前，HDAC 抑制剂的选择性抑制活性通常被认为对 Cap 基团与 HDAC6 结合位点之间的相互作用敏感，并且已经基于该策略设计和合成了大量选择性 HDAC6 抑制剂。然而，一些没有 Cap 基团的抑制剂也可以对 HDAC6 表现出优异的效力和选择性抑制作用，在这项研究中，BRD9757 和化合物 8 作为无帽选择性 HDAC6 抑制剂，被选为分子探针，以探索它们在 HDAC1&6 中的结合相互作用的差异。通过对 1μs 分子动力学模拟后的结合自由能和构象重排的分析，可以了解到，尽管结合位点中的残基保持高度一致，但 BRD9757 和化合物 8 在 HDAC1&6 中的结合机制不同，这将为发现新型选择性 HDAC6 抑制剂提供有价值的线索。
