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首页> 外文期刊>Medicinal chemistry research: an international journal for rapid communications on design and mechanisms of action of biologically active agents >Pharmacophore modeling, 3D-QSAR, and molecular docking study on naphthyridine derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1
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Pharmacophore modeling, 3D-QSAR, and molecular docking study on naphthyridine derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1

机译：萘啶衍生物作为3-磷酸肌醇依赖性蛋白激酶-1抑制剂的药效学建模，3D-QSAR和分子对接研究

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摘要

The 3-phosphoinositide-dependent protein kinase-1 (PDK1) is an imminent target for discovering novel anti-cancer drags. In order to understand the structure-activity correlation of naphthyridine-based PDK-1 inhibitors, we have carried out a combined pharmacophore, three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular docking studies. The study has resulted in six point pharmacophore models with four hydrogen bond acceptors (A), one hydrogen bond donor (D), and one aromatic ring (R) are used to derive a predictive atom-based 3D-QSAR model. The generated 3D-QSAR model shows that the alignment has good correlation coefficient for the training set compounds which comprises the values of R2 = 0.96, SD = 0.2, and F = 198.2. Test set compounds shows Q2 = 0.84, RMSE = 0.56, and Pearson-R = 0.84. The external validation was carried out to validate the predicted QSAR model which shows good predictive power of R2 ~(m) = 0.83 and k = 1.01, respectively. The external validation results also confirm the fitness of the model. The results indicated that, atom-based 3D-QSAR models and further modifications in PDK1 inhibitors via pharmacophore hypothesis are rational for the prediction of the activity of new inhibitors in prospect of drug design.
机译：3-磷酸​​肌醇依赖性蛋白激酶-1（PDK1）是发现新型抗癌药物的迫在眉睫的目标。为了了解基于萘啶的PDK-1抑制剂的构效关系，我们进行了组合药效团，三维定量构效关系（3D-QSAR）和分子对接研究。这项研究得出了具有四个氢键受体（A），一个氢键供体（D）和一个芳香环（R）的六点药效团模型，用于推导基于原子的预测3D-QSAR模型。生成的3D-QSAR模型表明，比对具有良好的相关性，可用于训练集化合物，包括R2 = 0.96，SD = 0.2和F = 198.2的值。测试集化合物显示Q2 = 0.84，RMSE = 0.56和Pearson-R = 0.84。进行了外部验证，以验证预测的QSAR模型，该模型分别显示R2〜（m）= 0.83和k = 1.01的良好预测能力。外部验证结果也证实了模型的适用性。结果表明，基于原子的3D-QSAR模型以及通过药效团假说对PDK1抑制剂进行的进一步修饰对于预测新型抑制剂在药物设计中的活性是合理的。

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