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Research Article

Apo和结合MDM2蛋白的动态特征揭示了抑制剂识别抗癌活性的机制

卷 30, 期 10, 2023

发表于: 24 October, 2022

页: [1193 - 1206] 页: 14

弟呕挨: 10.2174/0929867329666220610194919

价格: $65

摘要

背景：小鼠双分钟 2 同系物 (MDM2) 致癌蛋白是 p53 肿瘤抑制基因的主要细胞拮抗剂。通过在分子水平上抑制 MDM2-P53 相互作用来恢复 p53 活性，由于其有前途的抗癌作用，已成为癌症研究的基石。天然医药产品具有多种化学结构，是药物发现的重要来源。 α-山竹素 (AM) 和藤黄酸 (G250) 是植物来源的化合物，在体外和体内对 MDM2-P53 相互作用显示出抑制作用。 方法：尽管许多临床研究对 α-山竹素和藤黄酸与 MDM2 结合所表现出的结构机制的分子理解进行了更深入的了解，但仍然至关重要。在这项研究中，对每个 Apo 和结合的 p53 和 MDM2 蛋白进行了比较分子动力学模拟，以阐明 MDM2-p53 相互作用并更好地了解抑制机制。 结果：结果揭示了 MDM2-p53 相互作用裂缝内 AM 和 G250 的原子相互作用。这两种化合物都介导 p53 氨基末端结构域的 α 螺旋基序之间的相互作用，这导致正交相对残基之间的显着分离，特别是分别是 p53 和 MDM2 的 Lys8 和 Gly47 残基。在 AM 和 G250（分别为 ~0.04 nm 和 ~2.3 nm）的每个残基波动中观察到幅度的对比变化。回转半径（分别为 ~0.03 nm 和 0.04 nm）、C-alpha 偏差（分别为 ~0.06 nm 和 0.1 nm）。发现 AM 的酚基与 MDM2 的 Glu28 和 His96 残基建立了氢相互作用。 G250 的三氧六环也与 MDM2 的 Lys51 和 Leu26 残基形成氢键相互作用。 结论：利用本研究中每种化合物所采用的抑制结合模式所提供的信息，可能进一步有助于癌症治疗的定制设计。

关键词: MDM2，p53，α-倒捡子素（AM），甘博酸（G250），抗癌，动力学模拟

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