新型腺嘌呤类化合物的抗血小板凝集3D-QSAR研究

3D-QSAR study of novel adenine derivatives with antiplatelet aggregation activity

血小板凝集导致的血栓类心血管疾病正严重威胁着人类健康,故而抵抗血小板凝集对血栓类心血管疾病的治疗至关重要。嘌呤衍生物是具有抗血小板凝集活性的重要分子,研究嘌呤结构与抗凝效果之间的关系,对治疗血栓类疾病药物的研发具有重要指导意义。本文采用自组织分子场(SOMFA)对29个新型腺嘌呤化合物结构与抗凝活性之间的关系进行3D-QSAR分析,建立最佳SOMFA模型,交叉验证系数r^2可达0.87,非交叉验证系数r_(cv)~2可达0.83,统计方差比F值为183.41,标准方差s仅为0.05,表明该模型有较好的预测能力。测试集的r^2_(pred)为0.886,表明该模型对外部化合物的药物活性具有较为可靠的预测能力。同时,立体场和静电场的三维网格图显示了取代基空间体积及电荷分布规律对活性的影响,为下一步预测、设计及合成活性更高的抗凝集嘌呤分子提供理论指导。

Cardiovascular disease caused by platelet aggregation is a serious threat to human health,so antiplatelet aggregation has great significance to treat the disease.Since,purine derivatives are important molecules with antiplatelet aggregation activity,it is very essential to study the relationship between purine structure and antiplatelet aggregation effect,which could help us to find antithrombotic drugs.In this paper,the 3 D-QSAR analysis among twenty nine adenine compounds was carried out to find the relationship between purine structure and antiplatelet effect through self-organized molecular field analysis(SOMFA).The optimal model was established,and cross-validation coefficient r2 can reach up to 0.87,the non-cross-validation coefficient rcv2 can reach to 0.83,the statistical variance ratio is 183.41,and the standard variance is only 0.05,which show the model has enough ability to predict the antiplatelet aggregation effect of purine derivatives.The r2 pred of the test set was 0.886,which indicates that the model has a reliable predictive performance for the activities of external compounds.Meanwhile,the effect of the volume and charge distribution was shown by 3 D grid of stereoscopic field and static electric field,providing theoretical guidance for predicting,designing,and synthesizing purine derivatives with more high antiplatelet activity.