The hypoxic tumor microenvironment is one of the major causes of the enhanced chemoresistant and radioresistant behavior of cancer cells. Therefore, the hypoxia-induced factor (HIF) pathway can be endorsed, for not only the malignant phenotype of the cells, but also its metastatic potential. Many drugs targeting the HIF pathways have failed in the clinical setting to demonstrate therapeutic efficacy. Such failures occur due to lack of specificity or redundancy in the complexity of tumor signaling/metabolism that can overcome the inhibitory effects. Another important factor is the letdown of the compound that can be accredited to lack of patient selection in the trials. Although many clinical trials have evaluated the efficacy of anticancer therapeutics and examined their effects on HIF levels, patients were not selected based on their HIF expression levels. If patients do not have elevated levels of HIF, then the therapeutics that target the HIF pathway may be less effective. In the present work, we have targeted HIF-2α of the HIF pathway. Ellagic acid (EA), a well-known anticancer compound and radiosensitizer, is used to inhibit the activity of HIF-2α. Our results show a very unique binding of EA with HIF-2α. Such new agents should be used in combination therapy and will hopefully overcome the resistance that may develop during initial treatment if the patient is identified to have enhanced expression of HIF-2α. Molecular dynamics studies followed solvation free energy calculations (molecular mechanics Poisson-Boltzmann surface area) for understanding the binding stability and per residue contribution. Our in silico data look promising and EA should be studied more in in vitro and in vivo for further analysis of its efficacy.

中文翻译：

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研究鞣花酸对HIF-2α的计算机抑制作用，以提高抗癌治疗效果。

缺氧的肿瘤微环境是癌细胞化学抗性和放射抗性增强的主要原因之一。因此，低氧诱导因子（HIF）途径不仅可以用于细胞的恶性表型，而且可以用于转移潜能，因此可以被认可。许多靶向HIF途径的药物在临床环境中未能证明治疗效果。此类失败的发生是由于缺乏可以克服抑制作用的肿瘤信号/代谢复杂性的特异性或冗余性。另一个重要因素是可以在试验中选择缺乏患者的化合物，这一点令人失望。尽管许多临床试验已经评估了抗癌疗法的功效并检查了其对HIF水平的影响，未根据HIF表达水平选择患者。如果患者的HIF水平没有升高，那么靶向HIF途径的疗法可能效果不佳。在目前的工作中，我们已针对HIF途径的HIF-2α。鞣花酸（EA）是一种众所周知的抗癌化合物和放射增敏剂，用于抑制HIF-2α的活性。我们的结果表明EA与HIF-2α的结合非常独特。此类新药应用于联合治疗，如果确定患者的HIF-2α表达增强，有望克服其在初始治疗期间可能产生的耐药性。分子动力学研究遵循溶剂化自由能计算（分子力学泊松-玻耳兹曼表面积），以了解结合稳定性和每个残基的贡献。