Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship.
Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship.
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DOI：
10.1371/journal.pone.0161111
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Caballero J
中科院分区：
文献类型：
--
作者：
Navarro-Retamal C;Caballero J
在过去的几年里，黄酮类化合物与蛋白激酶（PKs）的相互作用已经用晶体学实验描述。有趣的是，一种黄酮类化合物在不同的PK中有不同的取向，不同的化学取代导致一个PK中黄酮类化合物支架的取向不同。因此，新的类似物的取向预测可以帮助设计具有高PK抑制活性的黄酮类化合物。考虑到这一点，我们通过对接实验研究了37种黄酮类化合物（黄酮和查尔酮）在周期蛋白依赖性PK CDK1中的结合模式。我们发现所研究的化合物采用了两种不同的取向进入CDK1的活性位点（手稿中的取向I和II）。此外，利用CoMFA和CoMSIA方法建立了定量构效关系（QSAR）模型来解释所研究的黄酮类化合物对CDK1抑制活性的变化趋势。使用了基于模板和基于对接的校准。从对接对齐开始建立的模型用于描述整个数据集和具有取向i的化合物，每种方法都获得了足够的R2和Q2值；有趣的是，只有疏水和氢键供体领域描述了黄酮类化合物作为CDK1抑制剂的不同效力，无论是对定义的序列还是亚群。我们目前的对接和QSAR结合应用揭示了设计具有增强PK抑制活性的新型类黄酮的重要因素。
In the last years, the interactions of flavonoids with protein kinases (PKs) have been described by using crystallographic experiments. Interestingly, different orientations have been found for one flavonoid inside different PKs and different chemical substitutions lead to different orientations of the flavonoid scaffold inside one PK. Accordingly, orientation predictions of novel analogues could help to the design of flavonoids with high PK inhibitory activities. With this in mind, we studied the binding modes of 37 flavonoids (flavones and chalcones) inside the cyclin-dependent PK CDK1 using docking experiments. We found that the compounds under study adopted two different orientations into the active site of CDK1 (orientations I and II in the manuscript). In addition, quantitative structure–activity relationship (QSAR) models using CoMFA and CoMSIA methodologies were constructed to explain the trend of the CDK1 inhibitory activities for the studied flavonoids. Template-based and docking-based alignments were used. Models developed starting from docking-based alignment were applied for describing the whole dataset and compounds with orientation I. Adequate R2 and Q2 values were obtained by each method; interestingly, only hydrophobic and hydrogen bond donor fields describe the differential potency of the flavonoids as CDK1 inhibitors for both defined alignments and subsets. Our current application of docking and QSAR together reveals important elements to be drawn for the design of novel flavonoids with increased PK inhibitory activities.