Metabolic reprogramming is a key attribute of cancer progression. An altered expression of pyruvate kinase M2 (PKM2), a phosphotyrosine-binding protein is observed in many human cancers. PKM2 plays a vital role in metabolic reprogramming, transcription and cell cycle progression and thus is deliberated as an attractive target in anticancer drug development. The expression of PKM2 is essential for aerobic glycolysis and cell proliferation, especially in cancer cells, facilitating selective targeting of PKM2 in cell metabolism for cancer therapeutics. We have screened a virtual library of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database of Indian medicinal plants to identify potential activators of PKM2. The initial screening was carried out for the physicochemical properties of the compounds, and then structure-based molecular docking was performed to select compounds based on their binding affinity towards PKM2. Subsequently, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, PAINS (Pan-assay interference compounds) patterns, and PASS evaluation were carried out to find more potent hits against PKM2. Here, Tuberosin was identified from the screening process bearing appreciable binding affinity toward the PKM2-binding pocket and showed a worthy set of drug-like properties. Finally, molecular dynamics simulation for 100 ns was performed, which showed decent stability of the protein-ligand complex and relatival conformational dynamics throughout the trajectory. The study suggests that modulating PKM2 with natural compounds is an attractive approach in treating human malignancy after required validation.

中文翻译：

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结构引导方法发现晚香玉素作为丙酮酸激酶 M2 的有效激活剂，靶向癌症治疗

代谢重编程是癌症进展的一个关键属性。在许多人类癌症中观察到丙酮酸激酶 M2 (PKM2)（一种磷酸酪氨酸结合蛋白）的表达发生改变。PKM2 在代谢重编程、转录和细胞周期进程中发挥着至关重要的作用，因此被认为是抗癌药物开发中一个有吸引力的靶点。PKM2 的表达对于有氧糖酵解和细胞增殖至关重要，尤其是在癌细胞中，有助于在癌症治疗的细胞代谢中选择性靶向 PKM2。我们从印度药用植物 IMPPAT（印度药用植物、植物化学和治疗学）数据库中筛选了一个植物化学物质虚拟库，以鉴定 PKM2 的潜在激活剂。对化合物的理化性质进行初步筛选，然后进行基于结构的分子对接，根据其与 PKM2 的结合亲和力来选择化合物。随后，进行了 ADMET（吸收、分布、代谢、排泄和毒性）特性、PAINS（泛测定干扰化合物）模式和 PASS 评估，以找到针对 PKM2 的更有效的命中。在这里，从筛选过程中鉴定出晚香玉素对 PKM2 结合袋具有明显的结合亲和力，并显示出一系列有价值的类似药物的特性。最后，进行了 100 ns 的分子动力学模拟，结果显示蛋白质-配体复合物在整个轨迹上具有良好的稳定性和相对构象动力学。该研究表明，经过必要的验证后，用天然化合物调节 PKM2 是治疗人类恶性肿瘤的一种有吸引力的方法。