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Identification of Novel Aurora Kinase A (AURKA) Inhibitors via Hierarchical Ligand-Based Virtual Screening
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2017-12-21 00:00:00 , DOI: 10.1021/acs.jcim.7b00300 Yue Kong 1, 2 , Andreas Bender 2 , Aixia Yan 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2017-12-21 00:00:00 , DOI: 10.1021/acs.jcim.7b00300 Yue Kong 1, 2 , Andreas Bender 2 , Aixia Yan 1
Affiliation
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Aurora kinases are essential for cell mitosis, amplified, and overexpressed in various human malignancies. Therefore, Aurora kinases have been promising targets for anticancer therapies, which has prompted an intensive search for their small-molecule inhibitors. In this work, we performed a hierarchical and time-efficient virtual screening cascade for scaffold hopping, aiming to obtain structurally novel and highly potent hit compounds targeting Aurora kinases. The cascade consisted of a shape- and an electrostatic-based protocol, combined with a QSAR-based selection protocol. This virtual screening cascade was used to screen two databases, one commercial database named the J&K database containing about 5.2 million diverse molecules and the Drugbank database. Experimental validations led to the identification of one structurally novel and highly potent hit compound (hit 1, found to possess an IC50 of 8.1 and 19 nM for Aurora kinases A and B, respectively), which can be a promising starting point for further exploration. Additionally, Aurora kinases were identified as off-targets for hits 2–6 (Crizotinib, CI-1033, Dasatinib, Bosutinib, MLN-518), which are approved or investigational drugs as listed in Drugbank, plausibly suggesting targeting Aurora kinases may even contribute to their mechanism of action.
中文翻译：
通过基于配体的虚拟筛选筛选新型Aurora激酶A（AURKA）抑制剂
极光激酶对于各种人类恶性肿瘤中的细胞有丝分裂，扩增和过表达都是必不可少的。因此，Aurora激酶已成为抗癌治疗的有希望的靶标，这促使人们对其小分子抑制剂进行了深入研究。在这项工作中，我们对支架跳跃进行了分级且省时的虚拟筛选级联，旨在获得靶向Aurora激酶的结构新颖且高效的命中化合物。级联由基于形状和静电的协议以及基于QSAR的选择协议组成。该虚拟筛选级联用于筛选两个数据库，一个名为J＆K数据库的商业数据库，其中包含约520万种不同分子，而Drugbank数据库则在其中。Aurora激酶A和B分别为8.1和19 nM的50 nM），这可能是进一步探索的有希望的起点。此外，Aurora激酶被确定为第2-6次击中的靶标（Crizotinib，CI-1033，Dasatinib，Bosutinib，MLN-518），这些药物已获批准或列为Drugbank中列出的研究用药物，有可能表明靶向Aurora激酶甚至可能有所贡献他们的作用机制。
更新日期：2017-12-21
中文翻译：
通过基于配体的虚拟筛选筛选新型Aurora激酶A（AURKA）抑制剂
极光激酶对于各种人类恶性肿瘤中的细胞有丝分裂，扩增和过表达都是必不可少的。因此，Aurora激酶已成为抗癌治疗的有希望的靶标，这促使人们对其小分子抑制剂进行了深入研究。在这项工作中，我们对支架跳跃进行了分级且省时的虚拟筛选级联，旨在获得靶向Aurora激酶的结构新颖且高效的命中化合物。级联由基于形状和静电的协议以及基于QSAR的选择协议组成。该虚拟筛选级联用于筛选两个数据库，一个名为J＆K数据库的商业数据库，其中包含约520万种不同分子，而Drugbank数据库则在其中。Aurora激酶A和B分别为8.1和19 nM的50 nM），这可能是进一步探索的有希望的起点。此外，Aurora激酶被确定为第2-6次击中的靶标（Crizotinib，CI-1033，Dasatinib，Bosutinib，MLN-518），这些药物已获批准或列为Drugbank中列出的研究用药物，有可能表明靶向Aurora激酶甚至可能有所贡献他们的作用机制。
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