Abstract：
Histone deacetylase 1 (HDAC1), a class I HDAC enzyme, is crucial for histone modification. Currently, it is emerged as one of the important biological targets for designing small molecule drugs through cancer epigenetics. Along with synthetic inhibitors different natural inhibitors are showing potential HDAC1 inhibitions. In order to gain insights into the relationship between the molecular structures of the natural inhibitors and HDAC1, different molecular modelling techniques (Bayesian classification, recursive partitioning, molecular docking and molecular dynamics simulations) have been applied on a dataset of 155 HDAC1 nature-inspired inhibitors with diverse scaffolds. The Bayesian study showed acceptable ROC values for both the training set and test sets. The Recursive partitioning study produced decision tree 1 with 6 leaves. Further, molecular docking study was processed for generating the protein ligand complex which identified some potential amino acid residues such as F205, H28, L271, P29, F150, Y204 for the binding interactions in case of natural inhibitors. Stability of these HDAC1-natutal inhibitors complexes has been also evaluated by molecular dynamics simulation study. The current modelling study is an attempt to get a deep insight into the different important structural fingerprints among different natural compounds modulating HDAC1 inhibition.Communicated by Ramaswamy H. Sarma.
摘要：
组蛋白脱乙酰酶1（HDAC1），一类HDAC酶，对于组蛋白修饰至关重要。目前,它已成为通过癌症表观遗传学设计小分子药物的重要生物学靶标之一。与合成抑制剂一起，不同的天然抑制剂显示出潜在的HDAC1抑制作用。为了深入了解天然抑制剂和HDAC1的分子结构之间的关系，不同的分子建模技术（贝叶斯分类，递归分区，分子对接和分子动力学模拟）已应用于155种具有不同支架的HDAC1自然启发抑制剂的数据集。贝叶斯研究显示了训练集和测试集两者的可接受的ROC值。递归分区研究产生了具有6片叶子的决策树1。Further,进行分子对接研究以生成蛋白质配体复合物，该复合物鉴定了一些潜在的氨基酸残基，例如F205，H28，L271，P29，F150，Y204，用于在天然抑制剂的情况下的结合相互作用。还通过分子动力学模拟研究评估了这些HDAC1-天然抑制剂复合物的稳定性。当前的建模研究试图深入了解调节HDAC1抑制的不同天然化合物之间的不同重要结构指纹。由RamaswamyH.Sarma沟通。
