Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing
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DOI：
10.1080/07391102.2019.1590241
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发表时间：
2020-01
影响因子：
4.4
通讯作者：
Jian Liu;Yehua Zhu;Yufang He;Haohao Zhu;Yi Gao;Zhi Li;Junru Zhu;Xinjie Sun;Fang Fang-Fang
中科院分区：
文献类型：
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作者：
Jian Liu;Yehua Zhu;Yufang He;Haohao Zhu;Yi Gao;Zhi Li;Junru Zhu;Xinjie Sun;Fang Fang-Fang
摘要组蛋白去乙酰化酶（HDAC）是一类重要的表观遗传酶家族，已成为抗肿瘤药物研究的一个重要靶点。在这里，我们描述了我们的虚拟筛选协议，通过药效团建模，3D-QSAR，分子对接和分子动力学（MD）模拟识别新的潜在的HDAC抑制剂。针对目前虚拟筛选工作的局限性，采用药物再利用策略来寻找可药用的HDAC抑制剂。建立了基于配体的药效团模型和3D-QSAR模型，并通过不同方法验证了模型的可靠性。然后，筛选DrugBank数据库，然后进行分子对接。进行MD模拟（100 ns）以进一步研究配体结合模式的稳定性。最后，结果表明具有高计算机模拟抑制效力的命中DB 03889适合于进一步的实验分析。作者：Ramaswamy H. Sarma
Abstract Histone deacetylases (HDACs), a critical family of epigenetic enzymes, has emerged as a promising target for antitumor drugs. Here, we describe our protocol of virtual screening in identification of novel potential HDAC inhibitors through pharmacophore modeling, 3D-QSAR, molecular docking and molecular dynamics (MD) simulation. Considering the limitation of current virtual screening works, drug repurposing strategy was applied to discover druggable HDAC inhibitor. The ligand-based pharmacophore and 3D-QSAR models were established, and their reliability was validated by different methods. Then, the DrugBank database was screened, followed by molecular docking. MD simulation (100 ns) was performed to further study the stability of ligand binding modes. Finally, results indicated the hit DB03889 with high in silico inhibitory potency was suitable for further experimental analysis. Communicated by Ramaswamy H. Sarma