槲皮素-3-O-磷酸对肺癌途径的肝药理活性
Heptapharmacological activity of Quercetin-3-O-phosphate against lung cancer pathways.
摘要(中文译文)
肺癌是全球癌症相关死亡的主要原因之一，吸烟是其主要危险因素，但环境暴露和基因突变也发挥重要作用。肺癌发生于肺部异常细胞不受控制地生长，全球每年新增病例超过200万例，死亡近180万例。耐药性，尤其是对靶向治疗的耐药性，是一项关键挑战，因为肿瘤常常发生适应并变得无反应。多靶点药物设计针对参与肿瘤生长的多条通路，为克服耐药性和提高治疗效果提供了有前景的解决方案。在本研究中，我们鉴定了若干肺癌相关蛋白：CK2、Ran-Importin β复合物、HNGF、人Survivin、CRK-II衔接蛋白、AKR1B10和tRNA二氢尿苷合酶2，其PDB ID分别为1JWH、1IBR、1SG1、1XOX、2DVJ、4XZL和4XP7。我们使用DrugBank库进行了分子对接，采用HTVS、SP和XP，随后用MM/GBSA进行构象处理。我们的多靶点对接分析鉴定出槲皮素-3-O-磷酸盐为最佳化合物，这是一种存在于洋葱、苹果、浆果、西兰花和柑橘等果蔬中的槲皮素衍生物。该化合物的对接评分和MM/GBSA评分分别为-5.835至-11.627 Kcal/mol和-14.28至-47.07 Kcal/mol，关键相互作用残基及其计数包括10ASP、9LEU、9LYS、7ALA、7ARG、7TYR、6GLN、5ASN、5GLU、5ILE和5VAL。我们还详细进行并分析了DFT和药代动力学，支持其进一步评估，因为它符合所有必需标准。我们进行了5 ns WaterMap模拟，确认了相互作用并突出了支持复合物稳定性的关键水合位点。使用TIP3P水模型的100 ns MD模拟显示偏差和波动极小，表明相互作用稳定，所用轨迹用于MM/GBSA计算，评估结合自由能，这增强了复合物的稳定性并有助于对最佳候选物进行排序。所有结果表明，槲皮素-3-O-磷酸盐在肺癌治疗方面具有强大潜力，但仍需实验验证以进行临床确认。
Abstract
Lung cancer is one of the leading causes of cancer-related deaths globally, with smoking being the primary risk factor, though environmental exposures and genetic mutations also play significant roles. Lung cancer arises when abnormal lung cells grow uncontrollably, leading to over 2 million new cases and nearly 1.8 million deaths globally. Drug resistance, especially to targeted therapies, is a key challenge, as tumours often adapt and become unresponsive. Multitargeted drug design, which targets multiple pathways involved in tumour growth, offers a promising solution to overcome resistance and improve treatment efficacy. In this study, we identified several lung cancer-associated proteins: CK2, Ran-Importin β complex, HNGF, Human Survivin, CRK-II adaptor protein, AKR1B10, and tRNA dihydrouridine synthase 2, with respective PDB IDs 1JWH, 1IBR, 1SG1, 1XOX, 2DVJ, 4XZL, and 4XP7. We conducted molecular docking using DrugBank's library, employing HTVS, SP, and XP, followed by pose processing with MM/GBSA. Our multitarget docking analysis identified Quercetin-3-O-Phosphate as the top compound, a quercetin derivative found in fruits and vegetables such as onions, apples, berries, broccoli, and citrus. The compound showed docking and MM/GBSA scores ranging from -5.835 to -11.627 Kcal/mol and -14.28 to -47.07 Kcal/mol, respectively, and the key interacting residues with their counts include 10ASP, 9LEU, 9LYS, 7ALA, 7ARG, 7TYR, 6GLN, 5ASN, 5GLU, 5ILE, and 5VAL. We also performed and analysed DFT and pharmacokinetics in detail, which supported its further evaluation as it met all the required criteria. We conducted a 5 ns WaterMap simulation, which confirmed the interactions and highlighted key hydration sites that support the complex's stability. A 100 ns MD simulation using the TIP3P water model showed minimal deviation and fluctuations, indicating stable interactions and the trajectories used for MM/GBSA calculations, assessing binding free, which reinforced the stability of the complexes and helped rank the best candidates. All results indicate that Quercetin-3-O-Phosphate holds strong potential for lung cancer treatment, though experimental validation is needed for clinical confirmation.
如何引用
AMA
Maryam Abdulrahman Alahdal, Hadil Alahdal, Najat Binothman, Majidah Aljadani, Nawal Helmi, Maryam A Al-Ghamdi, et al. Heptapharmacological activity of Quercetin-3-O-phosphate against lung cancer pathways.. PloS one. 2026; doi:10.1371/journal.pone.0349042.
APA
Maryam Abdulrahman Alahdal, Hadil Alahdal, Najat Binothman, Majidah Aljadani, Nawal Helmi, Maryam A Al-Ghamdi, et al (2026). Heptapharmacological activity of Quercetin-3-O-phosphate against lung cancer pathways.. PloS one. https://doi.org/10.1371/journal.pone.0349042
GB/T 7714
Maryam Abdulrahman Alahdal, Hadil Alahdal, Najat Binothman, Majidah Aljadani, Nawal Helmi, Maryam A Al-Ghamdi, et al. Heptapharmacological activity of Quercetin-3-O-phosphate against lung cancer pathways.[J]. PloS one, 2026 doi:10.1371/journal.pone.0349042.
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