从植物化合物中筛选出可靶向致癌蛋白KRAS的潜在抗癌药
In Silico Pharmacokinetic and Molecular Docking Studies of Natural Plants against Essential Protein KRAS for Treatment of Pancreatic Cancer
- 通过分子对接筛选50种植物化合物与KRAS结合能力
- 发现龙脑（borneol）结合能最低，且具备良好血脑屏障穿透性
- 适合对天然药物抗癌机制感兴趣的科研人员参考
胰腺导管腺癌（PDAC）是近年来导致死亡的主要原因之一。多项研究证实，致癌基因KRAS（Ki-ras2 Kirsten rat sarcoma viral oncogene）突变是胰腺癌的主要诱因。正常情况下KRAS作为细胞生长的开关，但突变后持续处于开启状态，导致细胞失控增殖并引发癌症。因此本研究将KRAS作为靶点。从50种植物源化合物中，通过分子对接评估其与KRAS结合口袋的结合能力，并利用计算方法预测其通过血脑屏障（BBB）的可能性。为预测配体的生物活性，构建了五种机器学习模型，最终选用表现最优的随机森林回归模型进行分析。结合能最低的六种化合物进一步评估其生物活性。同时分析了这些化合物的吸收、分布、代谢、排泄（ADME）特性。结果表明，龙脑（borneol）具有显著效果，显示出良好的治疗胰腺癌潜力。该化合物存在于薄荷、生姜、迷迭香等多种植物中，提示其在天然抗癌药物开发中具有重要意义。
原文摘要 · Abstract (English)
A kind of pancreatic cancer called Pancreatic Ductal Adenocarcinoma (PDAC) is anticipated to be one of the main causes of mortality during past years. Evidence from several researches supported the concept that the oncogenic KRAS (Ki-ras2 Kirsten rat sarcoma viral oncogene) mutation is the major cause of pancreatic cancer. KRAS acts as an on-off switch that promotes cell growth. But when the KRAS gene is mutated, it will be in one position, allowing the cell growth uncontrollably. This uncontrollable multiplication of cells causes cancer growth. Therefore, KRAS was selected as the target protein in the study. Fifty plant-derived compounds are selected for the study. To determine whether the examined drugs could bind to the KRAS complex's binding pocket, molecular docking was performed. Computational analyses were used to assess the possible ability of tested substances to pass the Blood Brain Barrier (BBB). To predict the bioactivity of ligands a machine learning model was created. Five machine learning models were created and have chosen the best one among them for analyzing the bioactivity of each ligand. From the fifty plant-derived compounds the compounds with the least binding energies are selected. Then bioactivity of these six compounds is analyzed using Random Forest Regression model. Adsorption, Distribution, Metabolism, Excretion (ADME) properties of compounds are analyzed. The results showed that borneol has powerful effects and acts as a promising agent for the treatment of pancreatic cancer. This suggests that borneol found in plants like mint, ginger, rosemary, etc., is a successful compound for the treatment of pancreatic cancer.
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