药效团
虚拟筛选
HDAC8型
组蛋白脱乙酰基酶
计算生物学
化学
组蛋白
对接(动物)
组蛋白脱乙酰基酶2
药物发现
药理学
生物化学
生物
医学
基因
护理部
作者
Xuben Hou,Jintong Du,Renshuai Liu,Yi Zhou,Minyong Li,Wenfang Xu,Hao Fang
摘要
As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC50 values (1.8–1.9 μM). Further studies demonstrated that compound H8-A5 was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for H8-A5, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment.
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