Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach.
Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach.
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DOI：
10.1038/s41598-021-97368-3
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发表时间：
2021-09-21
影响因子：
4.6
通讯作者：
Ul-Haq Z
中科院分区：
文献类型：
--
作者：
Ashraf S;Ranaghan KE;Woods CJ;Mulholland AJ;Ul-Haq Z
极光激酶B在细胞周期中发挥重要作用，协调有丝分裂过程。这种激酶的扩增和过表达与几种人类恶性肿瘤有关。因此，极光激酶B是一个潜在的抗癌药物靶点。本研究将基于原子的3D-QSAR分析和药效基团模型生成相结合，确定了可能抑制极光激酶b的乙酰脲醇衍生物的主要结构特征。所选择的CoMFA和CoMSIA模型的交叉验证值（q2）分别为0.68、0.641，线性回归值（r2）分别为0.971、0.933。这些值支持我们模型的统计可靠性。还生成了一个药效团模型，该模型结合了已报道的极光激酶b的晶体复杂结构的特征。药效团模型用于筛选商业数据库以检索潜在的先导候选物。基于药效团模型对每个阶段的命中结果进行多样性分析，然后根据它们与活性位点残基的相互作用和3D-QSAR预测进行分子对接和过滤。随后，进行了MD模拟和结合自由能计算来验证预测并表征分子水平上的相互作用。结果表明，鉴定的化合物保留了与结合残基的相互作用。结合能分解鉴定出B位点的Glu155、Trp156和Ala157残基以及C位点的Leu83和Leu207残基是结合亲和力的主要来源，与3D-QSAR结果互补。据我们所知，这是首次对WaterSwap油田和3D-QSAR地图进行比较。总的来说，这种综合策略为开发新的和潜在的AK-B抑制剂提供了基础，并适用于其他蛋白质靶点。
Aurora kinase B plays an important role in the cell cycle to orchestrate the mitotic process. The amplification and overexpression of this kinase have been implicated in several human malignancies. Therefore, Aurora kinase B is a potential drug target for anticancer therapies. Here, we combine atom-based 3D-QSAR analysis and pharmacophore model generation to identify the principal structural features of acylureidoindolin derivatives that could potentially be responsible for the inhibition of Aurora kinase B. The selected CoMFA and CoMSIA model showed significant results with cross-validation values (q2) of 0.68, 0.641 and linear regression values (r2) of 0.971, 0.933 respectively. These values support the statistical reliability of our model. A pharmacophore model was also generated, incorporating features of reported crystal complex structures of Aurora kinase B. The pharmacophore model was used to screen commercial databases to retrieve potential lead candidates. The resulting hits were analyzed at each stage for diversity based on the pharmacophore model, followed by molecular docking and filtering based on their interaction with active site residues and 3D-QSAR predictions. Subsequently, MD simulations and binding free energy calculations were performed to test the predictions and to characterize interactions at the molecular level. The results suggested that the identified compounds retained the interactions with binding residues. Binding energy decomposition identified residues Glu155, Trp156 and Ala157 of site B and Leu83 and Leu207 of site C as major contributors to binding affinity, complementary to 3D-QSAR results. To best of our knowledge, this is the first comparison of WaterSwap field and 3D-QSAR maps. Overall, this integrated strategy provides a basis for the development of new and potential AK-B inhibitors and is applicable to other protein targets.
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DOI：
10.3390/molecules26071981
发表时间：
2021-04-01
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Borah NA;Reddy MM
通讯作者：
Reddy MM
影响因子：
7.3
作者：
Adams, Nicholas D.;Adams, Jerry L.;Dhanak, Dashyant
通讯作者：
Dhanak, Dashyant
影响因子：
5.7
作者：
D'Alise, Anna Morena;Amabile, Giovanni;Cortese, Riccardo
通讯作者：
Cortese, Riccardo
影响因子：
19
作者：
Adams, RR;Carmena, M;Earnshaw, WC
通讯作者：
Earnshaw, WC
影响因子：
6
作者：
Ahmad, Sajjad;Murtaza, Uzair Ali;Azam, Syed Sikander
通讯作者：
Azam, Syed Sikander