Glutaminase plays an important role in carcinogenesis and cancer cell growth. This biological target is interesting against cancer cells. Therefore, in this work, in silico [docking and molecular dynamics (MD) simulations] and in vitro methods (antiproliferative and LC-MS metabolomics) were employed to assay a hybrid compound derived from glutamine and valproic acid (Gln-VPA), which was compared with 6-diazo-5-oxo-L-norleucine (DON, a glutaminase inhibitor) and VPA (contained in Gln-VPA structure). Docking results from some snapshots retrieved from MD simulations show that glutaminase recognized Gln-VPA and DON. Additionally, Gln-VPA showed antiproliferative effects in HeLa cells and inhibited glutaminase activity. Finally, the LC-MS-based metabolomics studies on HeLa cells treated with either Gln-VPA (IC60 = 8 mM) or DON (IC50 = 3.5 mM) show different metabolomics behaviors, suggesting that they modulate different biological targets of the cell death mechanism. In conclusion, Gln-VPA is capable of interfering with more than one pharmacological target of cancer, making it an interesting drug that can be used to avoid multitherapy of classic anticancer drugs.

中文翻译：

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HeLa 细胞上谷氨酰胺-丙戊酸 (Gln-VPA) 衍生物的分子建模和基于 LC-MS 的代谢组学。

谷氨酰胺酶在致癌作用和癌细胞生长中起重要作用。这种生物靶标对癌细胞很有趣。因此，在这项工作中，采用计算机 [对接和分子动力学 (MD) 模拟] 和体外方法（抗增殖和 LC-MS 代谢组学）来测定源自谷氨酰胺和丙戊酸 (Gln-VPA) 的杂合化合物，其与 6-diazo-5-oxo-L-norleucine（DON，一种谷氨酰胺酶抑制剂）和 VPA（包含在 Gln-VPA 结构中）进行了比较。从 MD 模拟中检索到的一些快照的对接结果表明，谷氨酰胺酶识别 Gln-VPA 和 DON。此外，Gln-VPA 在 HeLa 细胞中显示出抗增殖作用并抑制谷氨酰胺酶活性。最后，对用 Gln-VPA (IC60 = 8 mM) 或 DON (IC50 = 3) 处理的 HeLa 细胞进行基于 LC-MS 的代谢组学研究。5 mM) 显示不同的代谢组学行为，表明它们调节细胞死亡机制的不同生物学目标。总之，Gln-VPA 能够干扰多个癌症的药理学靶点，使其成为一种有趣的药物，可用于避免经典抗癌药物的多重治疗。