蛋白激酶CK2天然产物类抑制剂的定量构效关系研究

Quantitative structure⁃activity relationship studies on natural product inhibitors of protein kinase CK2

目的 构建CK2天然产物类抑制剂的定量构效关系(quantitative structure-activity relationship,QSAR)模型,揭示影响该类抑制剂活性的结构因素,为新型CK2抑制剂的开发提供理论基础和实验依据。方法 基于文献报道的115个多骨架CK2天然产物类抑制剂,采用遗传算法(genetic algorithm,GA)联合多元线性回归(multiple linear regression,MLR)方法,建立了基于优选的Dragon描述符的QSAR模型,以留一法交叉验证系数Q^(2)_(LOO)以及相关系数R^(2)作为模型内部验证的评价指标;通过Q^(2)_(ext)和R^(2)_(ext)评估模型的外部预测能力。结果 最优2D-QSAR模型由8个描述符组成,基于训练集内部验证的统计学参数为Q^(2)_(Loo)=0.7914、R^(2)=0.8220;基于测试集外部验证的统计学参数为Q^(2)_(ext)=0.792 1、R^(2)_(ext)=0.799 8,表明该模型具有较高的可靠性和预测能力。结论 影响CK2天然产物类抑制剂活性的分子描述符包括IVDE、CATS2D_08_DA、nArX、IC1、Chi_D/Dt、SdssC、F08[C-O]以及C-006。本研究可为新型CK2抗癌抑制剂的发现提供实验指导。

ObjectiveTo build the quantitative structure-activityy relationship model of CK2 natural products inhibitors,and to elucidate the underlying structural factors influencing their inhibitory activity.This study will provide the theoretical basis and experimental guidance for the development of new protein kinase CK2 inhibitors.MethodsBased on 115 CK2 natural product inhibitors with diverse chemical scaffolds reported in the published literature,genetic algorithm (GA) and multiple linear regression (MLR) methods,combined with preferred molecular descriptors calculated by Dragon,were employed to build the 2D-QSAR model.Theleave-one-out cross-validation coefficient Q^(2)_(LOO) and the correlation coefficient R^(2) were used as the evaluation indicators for the internal verification of the model,and the external predictive ability of the model was evaluated through Q^(2)_(ext) and R^(2)_(ext).ResultsThe best model composed of 8 molecular descriptors possessed Q^(2)_(Loo)=0.7914,R^(2)=0.8220 with leave one out cross-validation of training set and Q^(2)_(ext)=0.792 1,R^(2)_(ext)=0.799 8 of external validation,which indicated that the model had the robust reliability and high predictability.ConclusionsThe anti-CK2 activity of natural product inhibitors is mainly related to the descriptors IVDE CATS2D_08_DA,nArX,IC1,Chi_D/Dt,SdssC,F08[CO]and C-006.This study can provide experimental guidance for the discovery of novel CK2 anti-cancer inhibitors.