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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Computational investigation of imidazopyridine analogs as protein kinase B (Akt1) allosteric inhibitors by using 3D-QSAR, molecular docking and molecular dynamics simulations
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Computational investigation of imidazopyridine analogs as protein kinase B (Akt1) allosteric inhibitors by using 3D-QSAR, molecular docking and molecular dynamics simulations

机译：使用3D-QSAR，分子对接和分子动力学模拟来计算咪唑吡啶类似物作为蛋白激酶B（AKT1）变构抑制剂的计算研究

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Protein kinase B (Akt1), which is a pivotal node in various cellular signaling pathways and up-regulated in many human tumors, has been regarded as a promising target to discover novel anticancer candidates. In this research, molecular modeling methods including molecular docking, three-dimensional quantitative structure-activity relationship (3 D-QSAR) and molecular dynamics (MD) simulation were applied on a series of Akt1 allosteric inhibitors to explore the structural requirements for their activities. Molecular docking study was performed to collect the binding mode of Akt1 with its inhibitors. Subsequently, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3 D-QSAR model. The Q(2) and R-2 values of the best CoMFA model were calculated as 0.612 and 0.992, while those for the best CoMSIA model were calculated as 0.595 and 0.991, which verified the accuracy of the models. Based on the contour maps, 15 novel Akt1 inhibitors were designed and all of them exhibited better predicted activities than the most active compound in the dataset. MD simulations were implemented to evaluate the stability of the complexes under physiological conditions and the results were congruent with molecular docking. Finally, binding free energy was calculated through molecular mechanics generalized born surface area (MM-GBSA) approach. The results were consistent with the bioactivities, which revealed that van der Waals and coulomb energy made the most contribution during the molecular binding process. In a word, our research provided a significant insight for further discovery of potent Akt1 allosteric inhibitors.
机译：蛋白激酶B（Akt1）是多种细胞信号通路中的关键节点，在许多人类肿瘤中表达上调，被认为是发现新的抗癌候选物的一个有希望的靶点。本研究采用分子对接、三维定量构效关系（3D-QSAR）和分子动力学（MD）模拟等分子建模方法，对一系列Akt1变构抑制剂进行了研究，以探索其活性的结构要求。进行分子对接研究以收集Akt1与其抑制剂的结合模式。随后，采用比较分子场分析（CoMFA）和比较分子相似指数分析（CoMSIA）建立了三维定量构效关系模型。最佳CoMFA模型的Q（2）和R-2值分别为0.612和0.992，而最佳CoMSIA模型的Q（2）和R-2值分别为0.595和0.991，验证了模型的准确性。根据等高线图，设计了15种新型Akt1抑制剂，它们都比数据集中最活跃的化合物表现出更好的预测活性。通过分子动力学模拟，评估了配合物在生理条件下的稳定性，结果与分子对接一致。最后，通过分子力学广义玻恩表面积（MM-GBSA）方法计算了结合自由能。结果与生物活性一致，表明范德华能和库仑能在分子结合过程中贡献最大。总之，我们的研究为进一步发现有效的Akt1变构抑制剂提供了重要启示。

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