Gill Balraj Singh, Kumar Sanjeev
1 Centre for Biosciences, Central University of Punjab, Bathinda, India.
2 Centre for Plant Sciences, Central University of Punjab, Bathinda, India.
Tumour Biol. 2017 Mar;39(3):1010428317695530. doi: 10.1177/1010428317695530.
Lung cancer causes huge mortality worldwide, and targeting new pathway may provide an alternative in modulating signaling in cancer. Nuclear factor erythroid 2-related factor 2 is the major regulator of endogenous and exogenous stress by activating numerous antioxidant genes critical in cancer, Alzheimer's, Parkinson's, and inflammatory bowel diseases. Ganoderic acid is a triterpene from basiodiomycetes fungus Ganoderma lucidum with numerous therapeutic effects. In this study, ganoderic acid and its 50 isomers and natural activators were docked by receptor-based molecular docking using Maestro 9.6 (Schrödinger Inc.) in the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 signaling pathway. The receptor-based molecular docking reveals the best binding interaction of nuclear factor erythroid 2-related factor 2 and ganoderic acid A with GScore (-9.69) (kcal/mol), Lipophilic EvdW (-1.83), Electro (-0.72), Glide emodel (-73.369), H bond (-1.1), molecular mechanics/generalized Born surface area (-75.541) with Leu 718, Asp 800, Cys 797 residues involved in hydrogen bonding. The calculated docking energy highlights the lipophilic, hydrogen bonding, pi-pi stacking interactions, and non-covalent bonding. Analysis showed the involvement of cysteine and serine residues which were crucial in the activation and translocation from cytoplasm to the nucleus in the nuclear factor erythroid 2-related factor 2 signaling process. The molecular docking tool QikProp analyzed the absorption, distribution, metabolism, excretion, and toxicity but needs some modifications in their structure to satisfy Lipinski's rule. Ganoderic acid A is a best docked isoform which inhibits the cell proliferation, viability, migration, and reactive oxygen species and messenger RNA expression of nuclear factor erythroid 2-related factor 2 in H460 cells.
肺癌在全球范围内导致巨大的死亡率，而针对新的信号通路可能为调节癌症信号传导提供一种替代方法。核因子红系2相关因子2通过激活众多对癌症、阿尔茨海默病、帕金森病和炎症性肠病至关重要的抗氧化基因，是内源性和外源性应激的主要调节因子。灵芝酸是一种来自担子菌纲真菌灵芝的三萜类化合物，具有多种治疗作用。在本研究中，使用Maestro 9.6（薛定谔公司）在类 Kelch 样 ECH 相关蛋白 1 - 核因子红系2相关因子2信号通路中，通过基于受体的分子对接对灵芝酸及其50种异构体和天然激活剂进行了对接。基于受体的分子对接揭示了核因子红系2相关因子2与灵芝酸A之间最佳的结合相互作用，其GScore为 -9.69（千卡/摩尔），亲脂性EvdW为 -1.83，静电作用为 -0.72，Glide emodel为 -73.369，氢键为 -1.1，分子力学/广义玻恩表面积为 -75.541，涉及氢键的残基为Leu 718、Asp 800、Cys 797。计算得到的对接能量突出了亲脂性、氢键、π-π堆积相互作用和非共价键。分析表明，半胱氨酸和丝氨酸残基参与了核因子红系2相关因子2信号传导过程中的激活以及从细胞质到细胞核的转运过程。分子对接工具QikProp分析了吸收、分布、代谢、排泄和毒性，但需要对其结构进行一些修改以满足Lipinski规则。灵芝酸A是对接效果最佳的异构体，它抑制H460细胞中的细胞增殖、活力、迁移以及活性氧和核因子红系2相关因子2的信使核糖核酸表达。
