Department of Biochemistry, Faculty of Life Sciences, University of Ilorin, Ilorin, Nigeria.
Department of Biochemistry, Faculty of Basic Medical Sciences, University of Medical Sciences Ondo, Ondo State, Nigeria.
Curr Drug Discov Technol. 2020;17(5):725-734. doi: 10.2174/1570163816666190705164756.
Recent studies have observed overexpression of histone deacetylase 7 (HDAC7) and overactivity of extracellular signal-regulated kinases 1/2 (ERK1/2) in many tumors; therefore, pharmacological interventions to inhibit overexpression of HDAC7 and overactivity of ERK1/2 in cancerous cells holds great promise in cancer treatment. The promising anticancer properties of artemisinin and artemisinin-derivatives (ARTs) have been validated by various experimental reports, including advanced pre-clinical trials.
Our aim in this in silico study is to identify additional inhibitors of HDAC7, ERK1 and ERK2 as potential anticancer drug agents and provide insight into the molecular level of interactions of such ligands relative to known standards.
To achieve this aim, the binding affinities of ulixertinib (the standard ERK inhibitor), apicidin (the standard HDAC7 inhibitor) as well as 49 ARTs for HDAC7, ERK1 and ERK2 were evaluated using AutodockVina. The molecular binding interactions of compounds with remarkable binding affinity for all the 3 target proteins, relative to their respective standards, were viewed with Discovery Studio Visualizer, BIOVIA, 2016.
Out of the 49 ARTs, our study identified 2 compounds, artemisinin dimer and artemisinin dimer hemisuccinate, as having higher binding affinities for all the target proteins compared to their respective standard inhibitors.
These findings suggest that artemisinin dimer and artemisinin dimer hemisuccinate could be promising anticancer drug agents, with better therapeutic efficacy than ulixertinib and apicidin for the treatment of cancer via inhibition of HDAC7, ERK1 and ERK2.
最近的研究观察到，许多肿瘤中组蛋白去乙酰化酶 7（HDAC7）表达过表达和细胞外信号调节激酶 1/2（ERK1/2）过度活跃；因此，抑制癌细胞中 HDAC7 的过表达和 ERK1/2 的过度活性的药物干预在癌症治疗中具有很大的前景。青蒿素及其衍生物（ARTs）的有前途的抗癌特性已被各种实验报告验证，包括高级临床前试验。
我们在这项计算机研究中的目的是鉴定 HDAC7、ERK1 和 ERK2 的其他抑制剂，作为潜在的抗癌药物，并深入了解这些配体相对于已知标准的分子水平相互作用。
为了实现这一目标，使用 AutodockVina 评估了 ulixertinib（标准 ERK 抑制剂）、apicidin（标准 HDAC7 抑制剂）以及 49 种 ARTs 对 HDAC7、ERK1 和 ERK2 的结合亲和力。使用 Discovery Studio Visualizer、BIOVIA、2016 观察与所有 3 种靶蛋白具有显著结合亲和力的化合物的分子结合相互作用，相对于它们各自的标准。
在 49 种 ARTs 中，我们的研究发现 2 种化合物，青蒿素二聚体和青蒿素二聚体半琥珀酸酯，与各自的标准抑制剂相比，对所有靶蛋白具有更高的结合亲和力。
这些发现表明，青蒿素二聚体和青蒿素二聚体半琥珀酸酯可能是有前途的抗癌药物，与 ulixertinib 和 apicidin 相比，通过抑制 HDAC7、ERK1 和 ERK2 治疗癌症具有更好的治疗效果。
