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Importance of protein flexibility in ranking ERK2 Type I1/2 inhibitor affinities: a computational study

机译：蛋白质灵活性在排名ERK2 I1 / 2抑制剂亲和力中的重要性：计算研究

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Extracellular-regulated kinase (ERK2) has been regarded as an essential target for various cancers, especially melanoma. Recently, pyrrolidine piperidine derivatives were reported as Type I ~(1/2) inhibitors of ERK2, which occupy both the ATP binding pocket and the allosteric pocket. Due to the dynamic behavior of ERK2 upon the binding of Type I ~(1/2) inhibitors, it is difficult to predict the binding structures and relative binding potencies of these inhibitors with ERK2 accurately. In this work, the binding mechanism of pyrrolidine piperidines was discussed by using different simulation techniques, including molecular docking, ensemble docking based on multiple receptor conformation, molecular dynamics simulations and free energy calculations. Our computational results show that the traditional docking method cannot predict the relative binding ability of the studied inhibitors with high accuracy, but incorporating ERK2 protein flexibility into docking is an effective method to improve the prediction accuracy. It is worth noting that the binding free energies predicted by MM/GBSA or MM/PBSA based on the MD simulations for the docked poses have the highest correlation with the experimental data, which highlights the importance of protein flexibility for accurately predicting the binding ability of Type I ~(1/2) inhibitors of ERK2. In addition, the comprehensive analysis of several representative inhibitors indicates that hydrogen bonds and hydrophobic interactions are of significance for improving the binding affinities of the inhibitors. We hope this work will provide valuable information for further design of novel and efficient Type I ~(1/2) ERK2 inhibitors.
机译：细胞外调节激酶（ERK2）被认为是各种癌症，特别是黑色素瘤的必要目标。最近，吡咯烷哌啶衍生物被报告为ERK2的I〜（1/2）抑制剂，其占据ATP装订口袋和变构袋。由于ERK2在I〜（1/2）抑制剂的结合时ERK2的动态行为，难以准确地预测这些抑制剂的结合结构和相对结合效应。在这项工作中，通过使用不同的仿真技术讨论了吡咯烷哌啶的结合机制，包括基于多个受体构象的分子对接，集合对接，分子动力学模拟和自由能计算。我们的计算结果表明，传统的对接方法不能预测所研究的抑制剂具有高精度的相对结合能力，而是将ERK2蛋白质柔韧到对接是提高预测准确性的有效方法。值得注意的是，基于MM / GBSA或MM / PBSA基于用于停靠的姿势的MD模拟预测的无限化能量与实验数据具有最高的相关性，这突出了蛋白质灵活性来准确预测结合能力的重要性ERK2的I〜（1/2）抑制剂。此外，若干代表性抑制剂的综合分析表明氢键和疏水性相互作用对改善抑制剂的结合亲和力具有重要意义。我们希望这项工作将提供有价值的信息，以进一步设计新颖和有效的I〜（1/2）ERK2抑制剂。

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