虚拟筛选
HDAC6型
药效团
组蛋白脱乙酰基酶
连接器
化学
活力测定
癌症研究
生物化学
计算生物学
生物
细胞
组蛋白
计算机科学
基因
操作系统
作者
Abdullahi Ibrahim Uba,Mariya Hryb,Mursalin Singh,Candice Bui-Linh,Annie Tran,J. M. Atienza,Sarah Misbah,Xiaoyang Mou,Chun Wu
出处
期刊:Life Sciences
[Elsevier]
日期:2024-02-01
卷期号:338: 122395-122395
标识
DOI:10.1016/j.lfs.2023.122395
摘要
Histone deacetylase 6 (HDAC6) contributes to cancer metastasis in several cancers, including triple-negative breast cancer (TNBC)-the most lethal form that lacks effective therapy. Although several efforts have been invested to develop selective HDAC6 inhibitors, none have been approved by the FDA. Toward this goal, existing computational studies used smaller compound libraries and shorter MD simulations. Here, we conducted a structure-based virtual screening of ZINC "Druglike" library containing 17,900,742 compounds using a Glide virtual screening protocol comprising various filters with increasing accuracy. The top 20 hits were subjected to molecular dynamics simulation, MM-GBSA binding energy calculations, and further ADMET prediction. Furthermore, enzyme inhibition assay and cell viability assay were performed on six available compounds from the identified hits. C4 (ZINC000077541942) with a good profile of predicted drug properties was found to inhibit HDAC6 (IC50: 4.7 ± 11.6 μM) with comparative affinity to that of the known HDAC6 selective inhibitor Tubacin (TA) in our experiments. C4 also demonstrated cytotoxic effects against triple-negative breast cancer (TNBC) cell line MDA-MB-231 with EC50 of 40.6 ± 12.7 μM comparable to that of TA (2-20 μM). Therefore, this compound, with pharmacophore features comprising a non-hydroxamic acid zinc-binding group, heteroaromatic linker, and cap group, is proposed as a novel HDAC6 inhibitor.
科研通智能强力驱动
Strongly Powered by AbleSci AI