Abstract：
Histone deacetylases constitute a group of enzymes that participate in several biological processes. Notably, inhibiting HDAC8 has become a therapeutic strategy for various diseases. The current inhibitors for HDAC8 lack selectivity and target multiple HDACs. Consequently, there is a growing recognition of the need for selective HDAC8 inhibitors to enhance the effectiveness of therapeutic interventions. In our current study, we have utilized a multi-faceted approach, including Quantitative Structure-Activity Relationship (QSAR) combined with Quantitative Read-Across Structure-Activity Relationship (q-RASAR) modeling, pharmacophore mapping, molecular docking, and molecular dynamics (MD) simulations. The developed q-RASAR model has a high statistical significance and predictive ability (Q2F1:0.778, Q2F2:0.775). The contributions of important descriptors are discussed in detail to gain insight into the crucial structural features in HDAC8 inhibition. The best pharmacophore hypothesis exhibits a high regression coefficient (0.969) and a low root mean square deviation (0.944), highlighting the importance of correctly orienting hydrogen bond acceptor (HBA), ring aromatic (RA), and zinc-binding group (ZBG) features in designing potent HDAC8 inhibitors. To confirm the results of q-RASAR and pharmacophore mapping, molecular docking analysis of the five potent compounds (44, 54, 82, 102, and 118) was performed to gain further insights into these structural features crucial for interaction with the HDAC8 enzyme. Lastly, MD simulation studies of the most active compound (54, mapped correctly with the pharmacophore hypothesis) and the least active compound (34, mapped poorly with the pharmacophore hypothesis) were carried out to validate the observations of the studies above. This study not only refines our understanding of essential structural features for HDAC8 inhibition but also provides a robust framework for the rational design of novel selective HDAC8 inhibitors which may offer insights to medicinal chemists and researchers engaged in the development of HDAC8-targeted therapeutics.
摘要：
组蛋白脱乙酰酶构成一组参与几种生物过程的酶。值得注意的是,抑制HDAC8已成为各种疾病的治疗策略。目前的HDAC8抑制剂缺乏选择性并靶向多种HDAC。因此,人们越来越认识到需要选择性HDAC8抑制剂来增强治疗性干预措施的有效性.在我们目前的研究中,我们采用了多方面的方法，包括定量结构-活动关系（QSAR）结合定量阅读-跨结构-活动关系（q-RASAR）建模，药效基团作图，分子对接,和分子动力学(MD)模拟。建立的q-RASAR模型具有较高的统计意义和预测能力(Q2F1:0.778,Q2F2:0.775)。详细讨论了重要描述符的贡献，以深入了解HDAC8抑制中的关键结构特征。最佳药效团假设表现出高回归系数（0.969）和低均方根偏差（0.944），强调正确定向氢键受体（HBA）的重要性，环芳族（RA），和锌结合基团（ZBG）在设计有效的HDAC8抑制剂中的特征。为了确认q-RASAR和药效基团作图的结果，对五种有效化合物（44、54、82、102和118）进行分子对接分析，以进一步了解与HDAC8酶相互作用至关重要的这些结构特征。最后,进行了最具活性的化合物(54,用药效团假说正确定位)和最不活性的化合物(34,用药效团假说不良定位)的MD模拟研究,以验证上述研究的观察结果。这项研究不仅完善了我们对HDAC8抑制的基本结构特征的理解，而且为合理设计新型选择性HDAC8抑制剂提供了一个强大的框架，这可能为从事HDAC8靶向疗法开发的药物化学家和研究人员提供见解。
