Background

Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) as a major phosphatase would affect the development of tumors by regulating several cellular processes, and is a significant potential target for cancer treatment.

Methods

In the present work, a series of pyridine derivatives possessing a wide range of inhibitory activity was employed to investigate the structural requirements by developing three dimensional quantitative structure–activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The results show that CoMFA (R²_cv = 0.646, R²_pred = 0.5587) and CoMSIA (R²_cv = 0.777, R²_pred = 0.7131) have excellent stability and predictability. The relationship between the inhibitory activity and structure of the inhibitors was analyzed by the derived contour maps. Furthermore, the QSAR models were validated by molecular docking and molecular dynamics simulations, which were also applied to reveal the potential molecular mechanism of these inhibitors.

Findings

It was found that Arg110, Asn216, Thr218, Thr252 and Pro490 play a crucial role in stabilizing the inhibitors. Additionally, MM/PBSA calculations provided the binding free energy were also conducted to explain the discrepancy of binding activities. Overall, the outcomes of this work could provide useful information and theoretical guidance for the development of novel and potent SHP2 inhibitors.

中文翻译：

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通过3D-QSAR、分子对接和MD模拟研究SHP2与吡啶衍生物之间的分子机制

背景

含有 Src 同源 2 (SH2) 的蛋白酪氨酸磷酸酶 2 (SHP2) 作为主要磷酸酶将通过调节多种细胞过程影响肿瘤的发展，并且是癌症治疗的重要潜在靶标。

方法

在目前的工作中，一系列具有广泛抑制活性的吡啶衍生物被用于通过使用比较分子场分析 (CoMFA) 和比较分子场分析 (CoMFA) 开发三维定量构效关系 (3D-QSAR) 模型来研究结构要求。相似性指数分析 (CoMSIA) 方法。结果表明，CoMFA (R ² _cv  = 0.646, R ² _pred  = 0.5587) 和 CoMSIA (R ² _cv  = 0.777, R ² _pred = 0.7131) 具有出色的稳定性和可预测性。通过导出的等高线图分析抑制活性与抑制剂结构之间的关系。此外，QSAR 模型通过分子对接和分子动力学模拟进行了验证，这也被应用于揭示这些抑制剂的潜在分子机制。

发现

发现Arg110、Asn216、Thr218、Thr252和Pro490在稳定抑制剂中起关键作用。此外，还进行了结合自由能的 MM/PBSA 计算以解释结合活性的差异。总的来说，这项工作的结果可以为开发新型有效的 SHP2 抑制剂提供有用的信息和理论指导。