糖蛋白IIb/IIIa受体拮抗剂三维构效关系研究

THREE DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF GPIIb/IIIa ANTAGONISTS

摘要: 目的：研究三维构效关系，建立药效模型，为设计新型糖蛋白IIb/IIIa受体拮抗剂提供指导。方法和结果：利用比较分子力场方法，建立了IIb/IIIa受体拮抗剂的三维定量构效模型。在比较分子力场分析中，利用拮抗剂晶体结构为模板，进行了多种分子叠合形式研究，建立了具有良好预测能力的三维定量构效关系模型，表征模型预测能力的交叉验证系数R_CV²＝0.834，传统相关系数R²＝0.988，F＝323.63，标准偏差SE（Standard Error of Estimate）＝0.135。结论：所得模型解释了已有的构效关系，系数等势图映射的受体性质与实验结果相一致，可以指导新的拮抗剂设计。

Abstract: AIM：To disclose the relationship between activity and structure of a new class of non-peptide fibrinogen receptor antagonists. METHODS AND RESULTS: A series of 16 GPIIb/IIIa antagonists were investigated with the aim of developing a 3D-QSAR model using comparative molecular field analysis(CoMFA). The active conformation and the alignment of the whole molecule were extracted from the sibrafiban crystal structure. The model shows higher ability to explain and predict the activity of GPIIb/IIIa antagonists, and cross-validated R_ev²=0.834, Non cross-validated R²=0.988, F=323.63, SE(standard error of estimate)=0.135. CONCLUSION: The 3D-model is consistent with the experiments.