Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Al-Quwayiyah, Riyadh, Saudi Arabia.
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
Int J Biol Macromol. 2024 Apr;265(Pt 2):131064. doi: 10.1016/j.ijbiomac.2024.131064. Epub 2024 Mar 20.
Protein kinases are an attractive therapeutic target for cardiovascular, cancer and neurodegenerative diseases. Cancer cells demand energy generation through aerobic glycolysis, surpassing "oxidative phosphorylation" (OXPHOS) in mitochondria. The pyruvate dehydrogenase kinases (PDKs) have many regulatory roles in energy generation balance by controlling the pyruvate dehydrogenase complex. Overexpression of PDKs is associated with the overall survival of cancer. PDK3, an isoform of PDK is highly expressed in various cancer types, is targeted for inhibition in this study. PDK3 has been shown to binds strongly with a natural compound, thymoquinone (TQ), which is known to exhibit anti-cancer potential. Detailed interaction between the PDK3 and TQ was carried out using spectroscopic and docking methods. The overall changes in the protein's structures after TQ binding were estimated by UV-Vis spectroscopy, circular dichroism and fluorescence binding studies. The kinase activity assay was also carried out to see the kinase inhibitory potential of TQ. The enzyme inhibition assay suggested an excellent inhibitory potential of TQ towards PDK3 (IC = 5.49 μM). We observed that TQ forms a stable complex with PDK3 without altering its structure and can be a potent PDK3 inhibitor which may be implicated in cancer therapy after desired clinical validation.
蛋白激酶是心血管疾病、癌症和神经退行性疾病的一个有吸引力的治疗靶点。癌细胞通过有氧糖酵解来产生能量，超过了线粒体中的“氧化磷酸化”（OXPHOS）。丙酮酸脱氢酶激酶（PDKs）通过控制丙酮酸脱氢酶复合物在能量产生平衡方面具有许多调节作用。PDKs 的过表达与癌症的总生存率相关。PDK3 是 PDK 的一种同工酶，在各种癌症类型中高度表达，是本研究的抑制靶点。PDK3 已被证明与一种天然化合物——百里醌（TQ）强烈结合，TQ 具有抗癌潜力。使用光谱和对接方法对 PDK3 和 TQ 之间的详细相互作用进行了研究。通过紫外-可见光谱、圆二色性和荧光结合研究估计了 TQ 结合后蛋白质结构的整体变化。还进行了激酶活性测定以观察 TQ 的激酶抑制潜力。酶抑制测定表明 TQ 对 PDK3 具有极好的抑制潜力（IC = 5.49 μM）。我们观察到 TQ 与 PDK3 形成稳定的复合物，而不会改变其结构，并且可能是一种有效的 PDK3 抑制剂，在经过理想的临床验证后可能会被用于癌症治疗。
