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基于Tomoper CoMFA方法对香豆素类苯扎酰胺类组蛋白去乙酰化酶抑制剂的3D-QSAR研究及分子设计
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Abstract:
组蛋白去乙酰化酶(HDACs)是一类蛋白酶，其对染色体的结构修饰和基因表达调控发挥着重要的作用，可以作为治疗癌症和其他疾病的治疗靶点。组蛋白去乙酰化酶抑制剂(HDACIs)可增加细胞内组蛋白的乙酰化程度，抑制肿瘤细胞的增殖。本文采用易位体比较分子力场(Tomoper CoMFA)方法对一系列以香豆素为基础的苯扎酰胺类化合物作为HDACs抑制剂的HCT116细胞系和A2780细胞系进行三维定量构效关系研究(3D-QSAR)，对生成的模型进行交叉验证和非交叉验证。HCT116细胞系交叉验证系数q2= 0.517，非交叉验证系数r2 = 0.880，A2780细胞系交叉验证系数q2 = 0.572，非交叉验证系数r2= 0.869。最后采用Topomer search技术在ZINC数据库中进行虚拟筛选，最终设计出16个具有更高活性的新型HDACIs化合物。
Histone deacetylases (HDACs), a class of proteases, play an important role in the structural modifi-cation of chromosomes and the regulation of gene expression, and can be used as therapeutic tar-gets for the treatment of cancer and other diseases. Histone deacetylase inhibitors (HDACIs) can in-crease intracellular histone acetylation and inhibit tumor cell proliferation. In this paper, a series of coumarin-based benzamide compounds as HDACs inhibitors HCT116 cell lines and A2780 cell lines were studied by using Tomoper CoMFA method for 3D-Quantitative structure-activity Relationship (3D-QSAR), and the generated models were cross-verified and non-cross-verified. HCT116 cell line cross validation coefficient q2= 0.517, non-cross validation coefficient r2 = 0.880, A2780 cell line cross validation coefficient q2= 0.572, non-cross validation coefficient r2= 0.869.Finally, Topomer Search technology was used to conduct virtual screening in ZINC database, and finally 16 new HDACIs compounds with higher activity were designed.
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