CBP/P300溴结构域联芳基类抑制剂三维定量构效关系研究  

3D-QSAR Studies on Biaryl-Type Inhibitors for the Bromodomains of CBP/P300

作　　者：曹洪玉[1] 吴艳华[1] 任聪 周兴智 蒋革[1] Cao Hongyu;Wu Yanhua;Ren Cong;Zhou Xingzhi;Jiang Ge(College of Life Science and Technology, Dalian University, Dalian 116622)

机构地区：[1]大连大学生命科学与技术学院,大连116622

出　　处：《化学通报》2018年第6期548-554,共7页Chemistry

基　　金：国家自然科学基金项目(21601025);辽宁省自然科学基金指导计划项目(201601049)资助

摘　　要：CREB结合蛋白(CBP)和与其高度同源的P300蛋白是组蛋白乙酰化酶的两个亚型,两者通过它们的溴结构域(bromodomain,BRD)与染色质结合,目前,CBP/P300已经成为人类在肿瘤靶点领域中的研究热点。本研究基于CBP/P300溴结构域联芳基类抑制剂建立三维定量构效关系,采用比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(Co MSIA)分别建立35个已知活性抑制剂的3D-QSAR模型,以确定CBP/P300溴结构域联芳基类抑制剂分子结构与生物活性之间的定量关系。Co MFA和Co MSIA模型活性数据p IC50的预测值与实验值基本一致,说明这两个模型具有较高的预测能力和统计学意义。根据Co MFA和Co MSIA模型所提供的立体场、静电场、疏水场、氢键给体场、氢键供体场等信息提出了改善此类抑制剂活性的药物设计思路,为指导设计具有更高活性的新分子和预测更加有效的CBP/P300溴结构域抑制剂提供理论依据。CREB-binding protein（ CBP） and the highly homologous P300 are two subtypes of histone acetylase,which can bind to chromatin through their bromodomain（ BRD）. The CBP/P300 have already become a hot topic in the field of cancer target for they play important roles in the occurrence and development of tumors. In this study,the three-dimensional quantitative structure-activity relationship（ 3 D-QSAR） was established based on the biaryl inhibitors for the bromodomain of CBP/P300. In order to determine the quantitative relationship between molecular structure and biological activity of biaryl inhibitors,the 3 D-QSAR models of 35 inhibitors were established with comparative molecular field analysis（ Co MFA） and comparative molecular similarity index analysis（ Co MSIA）.The predicted p IC50 values of Co MFA and Co MSIA models were basically consistent with the actual p IC50 values,indicating that both models had highly predictive ability and statistical significance. Information of steric,electrostatic,hydrophobic,hydrogen bond acceptor and donor fields provided by Co MFA and Co MSIA could propose novel drug design ideas to design more effective inhibitors with higher activity for the bromodomain of CBP/P300.

关 键 词：CBP/P300溴结构域 联芳基类抑制剂 三维定量构效关系 比较分子力场分析法 比较分子相似性指数分析法 

分 类 号：TQ460.1[化学工程—制药化工]