Anwar Saleha, Khan Shama, Hussain Afzal, Alajmi Mohamed F, Shamsi Anas, Hassan Md Imtaiyaz
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
South African Medical Research Council, Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Science, School of Pathology, University of the Witwatersrand, Johannesburg, 2193, South Africa.
ACS Omega. 2024 Jun 26;9(27):29633-29643. doi: 10.1021/acsomega.4c03001. eCollection 2024 Jul 9.
Protein kinases are involved in various diseases and currently represent potential targets for drug discovery. These kinases play major roles in regulating the cellular machinery and control growth, homeostasis, and cell signaling. Dysregulation of kinase expression is associated with various disorders such as cancer and neurodegeneration. Pyruvate dehydrogenase kinase 3 (PDK3) is implicated in cancer therapeutics as a potential drug target. In this current study, a molecular docking exhibited a strong binding affinity of myricetin to PDK3. Further, a 100 ns all-atom molecular dynamics (MD) simulation study provided insights into the structural dynamics and stability of the PDK3-myricetin complex, revealing the formation of a stable complex with minimal structural alterations upon ligand binding. Additionally, the actual affinity was ascertained by fluorescence binding studies, and myricetin showed appreciable binding affinity to PDK3. Further, the kinase inhibition assay suggested significant inhibition of PDK3 by myricetin, revealing an excellent inhibitory potential with an IC value of 3.3 μM. In conclusion, this study establishes myricetin as a potent PDK3 inhibitor that can be implicated in therapeutic targeting cancer and PDK3-associated diseases. In addition, this study underscores the efficacy of myricetin as a potential lead to drug discovery and provides valuable insights into the inhibition mechanism, enabling advancements in cancer therapeutics.
蛋白激酶与多种疾病相关，目前是药物研发的潜在靶点。这些激酶在调节细胞机制以及控制生长、体内平衡和细胞信号传导方面发挥着主要作用。激酶表达失调与多种疾病相关，如癌症和神经退行性疾病。丙酮酸脱氢酶激酶3（PDK3）作为一种潜在的药物靶点，在癌症治疗中具有重要意义。在本研究中，分子对接显示杨梅素与PDK3具有很强的结合亲和力。此外，一项100纳秒的全原子分子动力学（MD）模拟研究深入了解了PDK3-杨梅素复合物的结构动力学和稳定性，揭示了配体结合后形成了结构变化最小的稳定复合物。此外，通过荧光结合研究确定了实际亲和力，杨梅素对PDK3表现出明显的结合亲和力。进一步的激酶抑制试验表明，杨梅素对PDK3有显著抑制作用，其IC值为3.3 μM，显示出优异的抑制潜力。总之，本研究确定杨梅素是一种有效的PDK3抑制剂，可用于治疗癌症和与PDK3相关的疾病。此外，本研究强调了杨梅素作为药物研发潜在先导物的有效性，并为抑制机制提供了有价值的见解，推动了癌症治疗的进展。
