类黄酮抑制IP6Ks的3D-QSAR研究  

3D-QSAR study of flavonoids inhibiting IP6Ks

作　　者：王海香[1] 秦东亚 岳一珂 伯维晨 郑鑫 梁桂兆[2] WANG Hai-xiang;QIN Dong-ya;YUE Yi-ke;BO Wei-chen;ZHENG Xin;LIANG Gui-zhao(Guiyang Nursing Vocational College,Guiyang 550081,China;Key Laboratory of Biorheological Science and Technology,Ministry of Education,Bioengineering College,Chongqing University,Chongqing 400044,China)

机构地区：[1]贵阳护理职业学院,贵州贵阳550081 [2]重庆大学生物工程学院生物流变科学与技术教育部重点实验室,重庆400044

出　　处：《分子科学学报》2020年第3期191-197,共7页Journal of Molecular Science

基　　金：国家自然科学基金资助项目(31771975,31571782)。

摘　　要：采用基于R基团搜索技术的Topomer CoMFA建立了14个类黄酮类肌醇六磷酸激酶抑制剂的3D-QSAR模型,研究了类黄酮化合物对肌醇六磷酸激酶(IP6Ks)活性的抑制作用.该模型的主成分数为3,拟合与留一法交互验证的复相关系数以及F检验值分别为q2=0.842,qst2=0.26;r2=0.965,rst2=0.12;F=91.519.在此基础上通过Topomer Search进行分子片段筛选,对化合物8,14和6进行重新拼接设计,其预测活性可以分别提高12.76倍、9.27倍和62%.运用Surflex-dock分子对接法研究了实验数据中活性最高的化合物6和活性最低的化合物10与IP6Ks的PDB结构的作用机制,发现并验证了之前所建立的Topomer CoMFA模型构效关系分析研究的结果,进一步阐明了化合物6抑制活性更高的原因.结果表明,在类黄酮分子结构的C(5),C(7)和C(4′)位上,取代基团的大小和静电性质对其抑制活性产生重要的影响.本研究可能对以天然产物设计和合成具有更好生物活性的IP6Ks抑制剂具有指导作用.A 3D-QSAR model of 14 flavonoids as inositol hexaphosphate kinase inhibitors was established by Topomer CoMFA based on R-group search technology to study the inhibitory effect of flavonoids on the activity of inositol hexaphosphate kinases(IP6 Ks).The optimal principal component number of the model is 3. The multiple correlation coefficients of leaving-one method cross validation, fitting and F-test value are respectively: q2=0.842, qst2=0.26;r2=0.965, rst2=0.12;F=91.519. On this basis, the molecular fragments were screened by Topomer Search, and the reconstitution designs of molecules 8,14 and 6 were carried out. The predictive activities of these molecules could be increased by 12.76 times, 9.27 times and 62% respectively. Finally, Surflex-dock method was used to study the interaction mechanism between the highest activity molecule 6 and the lowest activity molecule 10 with the PDB structure of IP6 Ks.The results of structure-activity relationship analysis of Topomer CoMFA model established before were found and verified, and the reason for the higher inhibitory activity of molecule 6 was further clarified. The results showed that the size and electrostatic properties of substituted groups have an important effect on the inhibitory activity of flavonoids at C(5), C(7) and C(4′) positions. This study may have a guiding role in designing and synthesizing IP6 Ks inhibitors with better biological activity from natural products.

关 键 词：类黄酮 肌醇六磷酸激酶 Topomer CoMFA Topomer Search 分子对接 

分 类 号：O641[理学—物理化学]