基于微管蛋白和秋水仙碱结合位点化合物构建3D-药效团新模型及先导物虚拟筛选  

A New 3D-pharmacophore Model Based on Tubulin-colchicine Binding Site and Ligands for Virtual Screening of New Leads

作　　者：王晓锋[1] 秦炳杰[1] 谢蓝[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850

出　　处：《中国科学：生命科学》2011年第10期978-985,共8页Scientia Sinica(Vitae)

基　　金：国家自然科学基金(批准号:20472114和30930106)资助项目

摘　　要：基于作用于微管蛋白秋水仙碱结合位点的小分子抑制剂与生物靶标的复合晶体结构,采用分子模拟软件Discovery Studio 3.0的受体-配体药效团产生程序建立了系列3D药效团新模型(M1-M6),并用20个已知微管抑制剂验证了其可靠性.用新药效团模型对约10000个化合物的数据库进行了虚拟筛选,发现了一些潜在先导物.据此合成的二芳烃胺类新化合物20在抑制人白血细胞K562的初步实验中显示出了明显的细胞形态变化和抑制活性,对多种人癌细胞A549,KB,KBvin和DU145均有较强的抑制活性(GI500.17～1.02μmol/L),表明以此新构建的药效团模型进行理性设计和寻找新型抗癌先导物的方法具有一定的可行性.Based on the structures of the tubulin-colchicine binding site and ligands,a series of new 3D pharmacophore models（M1-M6） were constructed by using a new module in the molecular modeling software Discovery Studio,version 3.0.After validated by 20 known tubulin inhibitors,one of the new pharmacophore models（M1） was used to screen about 10000 compounds and discovered some potential lead compounds.A synthesized diaryamine compound 20,one the of predicted potential leads,was tested in human chronic myelogenous leukemia（K562） cell line,resulting in obviously inhibitory activity and morphologic change on cellularity.Compound 20 also exhibited high potency in the human tumor cell line panel（A549,KB,KBvin and DU145） with a GI50 value range from 0.17 to 1.02 ？mol/L.Therefore,these results indicate that the new 3D-pharmacophore model could serve as a useful tool to search and rationally design new anticancer agents that target the tubulin-colchicine binding site.

关 键 词：微管蛋白 秋水仙碱 药效团 虚拟筛选 

分 类 号：R914[医药卫生—药物化学]