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Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors
Si-yan Liao,Ti-fang Miao,Jin-can Chen,Hai-liang Lu,Kang-cheng Zheng*
Author NameAffiliationE-mail
Si-yan Liao School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, China  
Ti-fang Miao School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, China  
Jin-can Chen School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, China  
Hai-liang Lu School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, China  
Kang-cheng Zheng* School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, China ceszkc@mail.sysu.edu.cn 
Abstract:
Three-dimensional quantitative structure activity relationship (3D-QSAR) and docking stud-ies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the compar-ative molecular field analysis (CoMFA) for training set with significant statistical quality (R2=0.898) and predictive ability (q2=0.654) was established.The same model was further applied to predict pIC50 values of the compounds in test set,and the resulting predictive correlation coefficient R2(pred) reaches 0.816,further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very in-teresting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some impor-tant factors improving the activities of these compounds were discussed in detail and were summarized as follows: the substituents R3-R5 (on the phenyl ring) with higher electroneg-ativity, the substituent R6 with higher electropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.
Key words:  Arylthioindole derivative,Tubulin inhibitor,Quantitative structure activity relationship,Comparative molecular field analysis,Docking study
FundProject:
Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors
廖思燕,苗体方,陈锦灿,陆海亮,郑康成*
摘要:
对一系列具有抗人乳腺癌细胞系MCF-7生物活性的微管蛋白抑制剂─芳基硫代吲哚衍生物(arylthioindole),进行了三维定量构效关系(3D-QSAR)和对接(docking)研究. 在训练集中,建立了具有良好统计质量和预报能力的比较分子力场分析(CoMFA) 模型,其非交叉验证相关系数平方R2为0.898,交叉验证相关系数平方q2为0.654. 同时在测试集的验证中得到预测相关系数平方R2(pred)为0.816, 进一步表明了该模型具有较高的预测能力. 此外,通过对接研究,获得了这些化合物与微管蛋白作用的键合方式和构象,发现该系列化合物的CoMFA力场分布与对接结合位点上的三维拓朴结构相一致. 根据CoMFA和对接分析的结果,细致地讨论和总结了有利于提高或改进该类化合物活性的主要因素,即在取代基R3、R4和R5上引进高电负性的基团,在取代基R6上引进带有高电负性且大体积的基团,以及在取代基R7上引进小体积的基团等都是有利的. 基于这些研究结果,在理论上还设计了5个新的具有较高活性的化合物.
关键词:  芳基硫代吲哚,微管蛋白抑制剂,定量构效关系,比较分子力场分析,对接分析
DOI:10.1088/1674-0068/22/05/473-480
分类号: