Survivin小分子抑制剂的计算机虚拟筛选及初步活性研究

发布时间：2018-06-20 14:54

本文选题：生存素 + 小分子抑制剂　；参考：《中国药理学通报》2013年02期

【摘要】：目的通过计算机虚拟筛选,寻找生存素(survivin)的小分子抑制剂,并对其活性进行初步研究。方法基于sur-vivin与其抑制性配体Smac/Diablo复合物的三维结构,用分子对接的方法对含有149,214个小分子的三维结构数据库进行筛选。通过初步活性测定确定活性较高的化合物,进一步研究其对凋亡,细胞周期及活性氧产生的影响。利用分子图像学方法分析化合物与survivin之间的作用模式。结果通过能量打分并根据结构多样性和类药性原则,最终选择了35个化合物进行初步活性测定,其中有9个化合物显示出明显的抑制活性,3个化合物的半数抑制浓度在30μmol.L-1以下。选择其中活性最高的化合物1-19进行进一步研究,结果显示小剂量的1-19能够促进细胞的早期凋亡,诱导细胞内活性氧产生,导致细胞发生S和G2/M期阻滞。分子图像学分析显示活性最高的1-19能够与survivin配体结合区的71位天门冬氨酸形成两个稳定的氢键。结论通过计算机辅助药物设计、药理活性测试以及分子图像学分析,初步确定了一个针对survivin的全新的先导化合物,为今后survivin小分子抑制剂的研究奠定了基础。
[Abstract]:Objective to search for the small molecular inhibitor of survivin by computer virtual screening and to study its activity. Methods based on the three-dimensional structure of sur-vivin and its inhibitory ligand Smac-Diablo complex, the three-dimensional structure database containing 149214 small molecules was screened by molecular docking method. The active compounds were determined by preliminary activity determination, and their effects on apoptosis, cell cycle and production of reactive oxygen species were further studied. The interaction pattern between compound and survivin was analyzed by molecular image method. Results according to the principle of structural diversity and similar properties, 35 compounds were selected for preliminary activity determination by energy scoring. Among them, 9 compounds showed obvious inhibitory activity, and the half inhibitory concentration of 3 compounds was below 30 渭 mol 路L ~ (-1). The most active compound 1-19 was selected for further study. The results showed that small dose of 1-19 could promote the early apoptosis of cells, induce the production of reactive oxygen species in cells and induce cell arrest in S and G _ 2 / M phase. Molecular image analysis showed that 1-19 with the highest activity could form two stable hydrogen bonds with aspartic acid at position 71 in the binding region of survivin ligands. Conclusion through computer aided drug design, pharmacological activity test and molecular image analysis, a new leading compound for survivin was preliminarily identified, which laid a foundation for the study of small molecular inhibitors of survivin in the future.
【作者单位】：中国医学科学院北京协和医学院血液病医院(血液学研究所)实验血液学国家重点实验室;天津市口腔医院暨南开大学附属口腔医院实验研究中心;
【基金】：国家自然科学基金资助项目(No 30701012,81170512) 天津市应用基础研究重点项目(No 07JCZDJC04900) 高等学校博士学科点专项科研基金项目(No 20070023093)
【分类号】：R329.25

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