中文关键词: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 英文关键词:Bromodomains of CBP/P300, Biaryl-typeinhibitors, 3D-QSAR, CoMFA, CoMSIA 基金项目:国家自然青年科学基金（21601025）；辽宁省自然科学基金指导计划（201601049）

作者	单位	E-mail
曹洪玉	大连大学 生命科学与技术学院 大连 116622	caohongyu@foxmail.com
吴艳华	大连大学 生命科学与技术学院 大连 116622
任聪	大连大学 生命科学与技术学院 大连 116622
周兴智	大连大学 生命科学与技术学院 大连 116622
蒋革	大连大学 生命科学与技术学院 大连 116622	jiangge1004@163.com

摘要点击次数:1914 全文下载次数:0 中文摘要: 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(CoMFA)和比较分子相似性指数分析法(CoMSIA)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。CoMFA模型训练集的交叉验证系数q2=0.701，非交叉验证系数r2＝0. 851，标准偏差SE＝0. 289，显著系数F＝59.051；CoMSIA模型训练集的交叉验证系数q2＝0.629，非交叉验证系数r2＝0.909，标准偏差SE=0.230，显著系数F＝74.868，此外，CoMFA和CoMSIA模型活性数据pIC50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CoMFA和CoMSIA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。 英文摘要: 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 (3D-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 3D-QSAR models of 35 inhibitors were established with comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). The best CoMFA model obtained for the training set were statistically significant with cross-validation coefficient q2 of 0.701, the non-cross-validation correlation coefficient r2 of 0.851, the standard deviation of 0.289 and the significant coefficient F of 59.051. The best CoMSIA model obtained for the training set were statistically significant with cross-validation coefficient q2 of 0.629, the non-cross-validation correlation coefficient r2 with 0.909, the standard deviation with 0.230 and the significant coefficient F with 74.868. The predicted pIC50 values of CoMFA and CoMSIA models were basically consistent with the actual pIC50 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 CoMFA and CoMSIA could propose novel drug design ideas to design more effective inhibitors with higher activity for the bromodomain of CBP/P300. 查看全文查看/发表评论下载PDF阅读器 相关附件：版权转让声明书 -->