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首页> 外文期刊>RSC Advances >Rapid identification of dual p53-MDM2/MDMX interaction inhibitors through virtual screening and hit-based substructure search
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Rapid identification of dual p53-MDM2/MDMX interaction inhibitors through virtual screening and hit-based substructure search

机译：通过虚拟筛选和基于匹配的子结构搜索快速鉴定双重p53-MDM2 / MDMX相互作用抑制剂

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Multi-target agents have garnered great interest over the past decade for their favorable therapeutic efficacy and drug resistance profiles. Recently, dual inhibition of the p53 tumor suppressor interaction with its two negative regulators MDM2 and MDMX has become an attractive anticancer approach as it can induce sustained MDM2/MDMX antagonism and robust p53 activation. However, small molecule inhibitors with dual specificity against MDM2 and MDMX are difficult to design and are still scarce. To identify novel scaffolds for dual inhibition of the p53-MDM2/MDMX interactions, we developed two five-point pharmacophore models for filtering the 2012 National Cancer Institute database, from which molecular docking was conducted to identify dual inhibitors. We found 38 virtual hits and subjected them to a fluorescence polarization-based competitive binding assay, resulting in 10 active compounds of different scaffolds. To further expand the chemical diversity of the initial hits, we performed a hit-based substructure search and identified NSC148171 from pharmacophore 1 as the most potent dual-specificity inhibitor with Ki values for MDM2 and MDMX at 0.62 and 4.6 μM. All hits were subjected to inhibition assay of cancer cellular vitality and showed anti-proliferative activity roughly correlated with their Ki values. This work not only yields several novel scaffolds for further structural and functional optimization of dual-specificity inhibitors of the p53-MDM2/MDMX interactions, but also showcases the power of our computational methods for small molecule anticancer drug discovery.
机译：在过去的十年中，多靶点药物因其良好的治疗效果和耐药性而引起了极大的兴趣。最近，双重抑制p53肿瘤抑制因子与其两个负调控因子MDM2和MDMX的相互作用已成为一种有吸引力的抗癌方法，因为它可以诱导持续的MDM2 / MDMX拮抗作用和强大的p53激活。但是，对MDM2和MDMX具有双重特异性的小分子抑制剂很难设计，而且仍然很稀少。为了鉴定双重抑制p53-MDM2 / MDMX相互作用的新型支架，我们开发了两个五点药效团模型来过滤2012 National Cancer Institute数据库，从中进行分子对接来鉴定双重抑制剂。我们发现了38个虚拟命中，并对其进行了基于荧光偏振的竞争结合测定，得到10个不同支架的活性化合物。为了进一步扩大初始匹配的化学多样性，我们进行了基于匹配的亚结构搜索，并从药效基团1中鉴定出NSC148171是最有效的具有 K i < MDM2和MDMX的/ sub> 值分别为0.62和4.6μM。所有的命中都进行了癌细胞活力的抑制测定，并显示出与它们的 K i 值大致相关的抗增殖活性。这项工作不仅产生了几个新颖的支架，以进一步优化p53-MDM2 / MDMX相互作用的双特异性抑制剂的结构和功能，而且还展示了我们用于小分子抗癌药物发现的计算方法的强大功能。

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