Singh Shilpi, Meena Ashish, Luqman Suaib, Meena Abha
Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
Aristos Labs, 141 Stockmans Lane, BT9 7JE, Belfast, United Kingdom.
Food Chem Toxicol. 2021 May;151:112091. doi: 10.1016/j.fct.2021.112091. Epub 2021 Feb 26.
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 binding-energies 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.
与癌症基因相关的蛋白激酶在血管生成、侵袭、迁移、增殖和存活中发挥着至关重要的作用。因此，以植物化学物质靶向激酶进行癌症预防/治疗可能是一种有前景的方法。鉴于植物化学物质在调节癌症相关激酶方面的潜力，本研究旨在寻找所选黄酮类化合物在癌症化学预防/治疗方面的抑制前景。通过探索黄酮类化合物与参与不同致癌阶段的激酶（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，进行了分子对接相互作用分析。在黄酮类化合物中，刺槐素对JAK-2的结合能最高，其次是Fyn > VEGF > PI3K > MKK4 > MAPK > BRaf > STAT-5 > STAT-1 > STAT-4，而松属素与JAK-2的结合能较高，其次是B-Raf > MKK4 > VEGF > PI3K > MAPK > STAT-! > STAT-4 > STAT-5。此外，分子动力学模拟显示，松属素与JAK-2蛋白相互作用的结合能为-25.068±1.08 kJ/mol，而刺槐素与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。刺槐素和松属素的高结合能、低抑制常数和类药性为它们作为JAK-2抑制剂的使用提供了线索，这可能对基于分子/细胞靶点的体外和体内研究有用。
