摘要
Purpose: To design a dual inhibitor of natural origin capable of targeting ErbB1 and ErbB2 kinases for the treatment of lung cancer. Method: Advanced In silico drug designing techniques were explored in this study. Sequence and structure analysis of ErbB1 and ErbB2 was followed by three dimensional (3D) pharmacophore. The generated model was used for molecular docking simulation studies for predicting the best natural dual inhibitors, the selected inhibitors were subjected to absorption, distribution, metabolism, excretion and toxicology (ADME/Tox) prediction. Results: The results confirmedfive phytochemicals, viz. hyoscyamide, cannabisin F, cochinchinenene D, cannabisin E, and heliotropamide and five FDA approved drugs namely fesoterodine, antrafenine, fluspirilene, posaconazole, and iloprost to be potential inhibitors of both ErbB1 and ErbB2. The shortlisted compounds from both the panels were showing better MolDock score than the two reference drugs (Lapatinib and Afatinib). Conclusion: The 3D pharmacophore modelling and molecular docking simulations gave us ten compounds that successfully exploited dual inhibition of ErbB1 and ErbB2. With 8 and 12 hydrogen bonds with ErbB1 and ErbB2 respectively cannabisin F showed best interaction of all.
摘要译文
目的：设计一种天然来源的双重抑制剂，能够靶向ErbB1和ErbB2激酶，用于治疗肺癌。方法：本研究探索了先进的计算机药物设计技术。 ErbB1和ErbB2的序列和结构分析之后是三维（3D）药效团。生成的模型用于分子对接模拟研究以预测最佳天然双重抑制剂，所选择的抑制剂经受吸收，分布，代谢，排泄和毒理学（ADME / Tox）预测。结果：结果证实了五种植物化学物质，即。 hyoscyamide，cannabisin F，cochinchinenene D，cannabisin E和heliotropamide以及五种FDA批准的药物，即fesoterodine，antrafenine，fluspirilene，posaconazole和iloprost，是ErbB1和ErbB2的潜在抑制剂。来自两个小组的入选化合物显示出比两种参考药物（拉帕替尼和阿法替尼）更好的MolDock评分。结论：3D药效团建模和分子对接模拟为我们提供了10种成功利用ErbB1和ErbB2双重抑制的化合物。与ErbB1和ErbB2分别具有8和12个氢键，大麻素F显示出最佳的相互作用。
Hu, Jian-Bin; Dong, Ming-Jun & Zhang, Jun. A Holistic In silico Approach to Develop Novel Inhibitors Targeting ErbB1 and ErbB2 Kinases[J]. Tropical Journal of Pharmaceutical Research, 2016,15(02): 231-239