Bakri Ridla, Parikesit Arli Aditya, Satriyanto Cipta Prio, Kerami Djati, Tambunan Usman Sumo Friend
Bioinformatics Group, Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia, Depok 16424, Indonesia.
Mathematics Computation Group, Department of Mathematics, Faculty of Mathematics and Science, University of Indonesia, Depok 16424, Indonesia.
Adv Bioinformatics. 2014;2014:104823. doi: 10.1155/2014/104823. Epub 2014 Aug 24.
Histone deacetylase (HDAC) has a critical function in regulating gene expression. The inhibition of HDAC has developed as an interesting anticancer research area that targets biological processes such as cell cycle, apoptosis, and cell differentiation. In this study, an HDAC inhibitor that is available commercially, suberoyl anilide hydroxamic acid (SAHA), has been modified to improve its efficacy and reduce the side effects of the compound. Hydrophobic cap and zinc-binding group of these compounds were substituted with boron-based compounds, whereas the linker region was substituted with p-aminobenzoic acid. The molecular docking analysis resulted in 8 ligands with ΔG binding value more negative than the standards, SAHA and trichostatin A (TSA). That ligands were analyzed based on the nature of QSAR, pharmacological properties, and ADME-Tox. It is conducted to obtain a potent inhibitor of HDAC class II Homo sapiens. The screening process result gave one best ligand, Nova2 (513246-99-6), which was then further studied by molecular dynamics simulations.
组蛋白去乙酰化酶（HDAC）在调节基因表达中起关键作用。HDAC抑制已发展成为一个有趣的抗癌研究领域，其靶向细胞周期、细胞凋亡和细胞分化等生物学过程。在本研究中，一种市售的HDAC抑制剂——辛二酰苯胺异羟肟酸（SAHA）已被修饰，以提高其疗效并降低该化合物的副作用。这些化合物的疏水帽和锌结合基团被硼基化合物取代，而连接区被对氨基苯甲酸取代。分子对接分析产生了8种配体，其ΔG结合值比标准品SAHA和曲古抑菌素A（TSA）更负。基于定量构效关系的性质、药理特性和药物代谢动力学及毒性对这些配体进行了分析。目的是获得一种有效的人类II类HDAC抑制剂。筛选过程的结果产生了一种最佳配体Nova2（513246-99-6），然后通过分子动力学模拟对其进行了进一步研究。
