Acacetin and pinostrobin as a promising inhibitor of cancer-associated protein kinases
Acacetin and pinostrobin as a promising inhibitor of cancer-associated protein kinases
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DOI：
10.1016/j.fct.2021.112091
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发表时间：
2021-04-15
影响因子：
4.3
通讯作者：
Meena, Abha
中科院分区：
文献类型：
--
作者：
Singh, Shilpi;Meena, Ashish;Meena, Abha
与癌症基因相关的蛋白激酶在血管生成、侵袭、运动、增殖和存活中发挥着至关重要的作用。因此，用植物化学物质靶向激酶来预防/治疗癌症可能是一种有前途的方法。鉴于植物化学物质在调节癌症相关激酶方面的潜力，本研究旨在寻找选定的黄酮类化合物用于癌症化学预防/治疗的抑制前景。通过探索黄酮类化合物与参与不同癌变阶段的激酶（PI3K、Akt、mTOR、EGFR、MAPK、MKK4、Fyn、ZAP-70、B-Raf、JAK-2、STAT-1、STAT-3、STAT-4、STAT-5 和 VEGF）的结合潜力来进行分子对接相互作用分析。在黄酮类化合物中，金合欢素对 JAK-2 的结合能最高，依次为 Fyn > VEGF > PI3K > MKK4 > MAPK > BRaf > STAT-5 > STAT-1 > STAT-4，而松脂素与 JAK-2 的结合能较高，其次为 B-Raf > MKK4 > VEGF > PI3K > MAPK > STAT-1 > STAT-4 > STAT-5。此外，分子动力学模拟显示，松菌素与 JAK-2 蛋白相互作用的结合能为 25.068 +/- 1.08 kJ/mol，而金合欢素与 JAK-2 和 Fyn 相互作用的结合能分别为 -23.466 +/- 0.9508 kJ/mol 和 -8.935 +/- 1.3108 kJ/mol。金合欢素和松菌胺的高结合能、低抑制常数和药物相似性为它们作为 JAK-2 抑制剂的用途提供了线索，这可用于基于分子/细胞靶点的体外和体内研究。
Protein kinases associated with cancer genes play vital role in angiogenesis, invasion, motility, proliferation, and survival. Therefore, cancer prevention/treatment, targeting kinases with phytochemicals could be a promising approach. Given potential of phytochemicals in modulating cancer-associated kinases, present study aims to find inhibitory prospects of selected flavonoids for cancer-chemoprevention/treatment. The molecular docking interaction analysis was done by exploring binding potential of flavonoids with kinases (PI3K, Akt, mTOR, EGFR, MAPK, MKK4, Fyn, ZAP-70, B-Raf, JAK-2, STAT-1, STAT-3, STAT-4, STAT-5, and VEGF) involved in various carcinogenesis phases. Among flavonoids acacetin showed highest binding-energy against JAK-2 following Fyn > VEGF > PI3K > MKK4 > MAPK > BRaf > STAT-5 > STAT-1 > STAT-4 whereas pinostrobin depicts higher binding-energy with JAK-2 followed by B-Raf > MKK4 > VEGF > PI3K > MAPK > STAT-1 > STAT-4 > STAT-5. Further, molecular-dynamic simulation revealed that pinostrobin interacted with JAK-2 protein with binding-energy of 25.068 +/- 1.08 kJ/mol whereas acacetin interacted with both JAK-2 and Fyn with bindin-genergies of -23.466 +/- 0.9508 kJ/mol and -8.935 +/- 1.3108 kJ/mol respectively. High binding-energy, low inhibition-constant, and drug-likeness of acacetin and pinostrobin provide a clue for their usage as a JAK-2 inhibitor which could be useful for molecular/cell-target based in-vitro and in-vivo investigations.