Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
Laboratory of Drug Design and Discovery, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
SAR QSAR Environ Res. 2024 May;35(5):367-389. doi: 10.1080/1062936X.2024.2350504. Epub 2024 May 17.
Histone deacetylase 3 (HDAC3), a Zn-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.
组蛋白去乙酰化酶 3（HDAC3）是一种 Zn 依赖性的 I 类 HDAC，与多种疾病有关，如神经退行性疾病、糖尿病、心血管疾病、肾脏疾病和多种类型的癌症。因此，开发新型和选择性的 HDAC3 抑制剂可能是对抗这些疾病的有希望的方法。在这里，对一组 HDAC3 抑制剂进行了基于不同分类的分子建模研究，如贝叶斯分类、递归分区（RP）、SARpy 和线性判别分析（LDA），以确定对 HDAC3 抑制有贡献的基本结构要求，随后进行分子对接研究和分子动力学（MD）模拟分析。本研究揭示了羟肟酸功能对 Zn 螯合的重要性，以及与 Tyr298 残基的氢键相互作用。在贝叶斯分类、递归分区和 SARpy 模型中，羟肟酸功能对更高的 HDAC3 抑制的重要性得到了注意。此外，还揭示了噻唑环取代的重要性，而分子结构中存在线性烷基羧酸功能、任何类型的酯功能、苯并二氮䓬部分和甲氧基会对 HDAC3 抑制产生不利影响。因此，这项研究可以为未来设计和发现有效的新型 HDAC3 抑制剂提供帮助。
