Histone deacetylases (HDACs) play important roles in various biological processes, but are also notorious for their over-expression in numerous cancers and neurological disorders. Therefore, the development of isoform selective HDAC inhibitors is crucial in order to prevent any side effects of pan inhibition. This work focuses on identifying novel inhibitors for the selective inhibition of HDAC8, an isoform implicated in fatal diseases like T-cell lymphoma, colon cancer and childhood neuroblastoma. Virtual screening of the ‘In-trials’ subset of ZINC database has been carried out with the help of two pharmacophore models signifying potent and selective HDAC8 inhibition. A detailed molecular docking strategy, followed by molecular dynamics simulations and post-scoring with MM-GBSA calculations, has led to the identification of six promising molecules that have excellent binding with the HDAC8 active site. In order to establish the selectivity profile of these molecules, their binding to off-target HDAC isoforms has also been evaluated. Substitution analyses of the proposed inhibitors suggest that aromatic substituents that access the adjacent hydrophobic pocket of the HDAC8 active site have the potential to further enhance the HDAC8 selectivity.

组蛋白脱乙酰基酶（HDAC）在各种生物学过程中都起着重要作用，但由于它们在多种癌症和神经系统疾病中的过度表达而臭名昭著。因此，为了防止泛抑制的任何副作用，开发同工型选择性HDAC抑制剂至关重要。这项工作的重点是确定选择性抑制HDAC8的新型抑制剂，HDAC8是一种与致命疾病有关的同种型，如T细胞淋巴瘤，结肠癌和儿童神经母细胞瘤。ZINC数据库“试验中”子集的虚拟筛选已借助两种表示有效和选择性HDAC8抑制的药效基团模型进行了。详细的分子对接策略，然后进行分子动力学模拟和MM-GBSA计算后评分，已经鉴定出六个与HDAC8活性位点具有优异结合力的有前途的分子。为了建立这些分子的选择性图谱，还评估了它们与脱靶HDAC同工型的结合。拟议中的抑制剂的取代分析表明，接近HDAC8活性位点相邻疏水口袋的芳族取代基有可能进一步提高HDAC8的选择性。