基于comfa的激动剂在重组D1 vs D2多巴胺受体亲和力的预测。
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Wilcox RE, Tseng T, Brusniak MY, Ginsburg B, Pearlman RS, Teeter M, DuRand C, Starr S, Neve KA
基于comfa的激动剂在重组D1 vs D2多巴胺受体亲和力的预测。
中华医学化学杂志1998 10月22日;41(22):4385-99。
- PubMed ID
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9784114 (PubMed视图］
- 摘要
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我们之前已经证明，在三维定量结构-活性关系研究(3D-QSAR)中，使用激动剂对克隆细胞中选择性表达的重组受体的亲和力作为因变量，为测量的准确性和精确性提供了独特的机会。因此，在两种不同的重组多巴胺受体上比较一组化合物的亲和性结构决定因素代表了3D-QSAR可实现的目标。通过与D1受体的高亲和力模板化合物3-烯丙基-6-溴-7,8-二羟基-1-苯基- 2,3,4,5 -四氢- 1h -苯氮平进行配位，建立了16种结构不同的激动剂结合构象的分子数据库。根据D2受体溴隐亭的第二个模板，建立了相同化合物结合构象的第二个分子数据库。这些排列的结构表明了两种多巴胺受体的三点药效图谱(一个阳离子氮和两个电负性中心)，其主要差异在于氮在儿茶酚环平面上的高度和氢键区域的性质。在C6胶质瘤细胞中稳定表达的重组D1和D2多巴胺受体上的低亲和力激动剂结合构象的ln(1/KL)值被用作16个排列结构的CoMFA(比较分子场分析)的目标特性。由此产生的CoMFA模型产生了交叉验证的R2 (q2)值(预测的标准误差)为0。D1和D2亲和度分别为879(1.471,5个主成分)和0.834(1.652,5个主成分)。D1和D2受体的简单R2值(估计的标准误差)分别为0.994(0.323)和0.999(0.116)。D1和D2模型F值分别为341和2465,df分别为5和10。 The predictive utility of the CoMFA model was evaluated at both receptors using the dopamine agonists, apomorphine and 7-OH-DPAT. Predictions of KL were accurate at both receptors. Flexible 3D searches of several chemical databases (NCI, MDDR, CMC, ACD, and Maybridge) were done using basic pharmacophore models at each receptor to determine the similarity of hit lists between the two models. The D1 and D2 models yielded different lists of lead compounds. Several of the lead compounds closely resembled high-affinity training set compounds. Finally, homology modeling of agonist binding to the D2 receptor revealed some consistencies and inconsistencies with the CoMFA-derived D2 model and provided a possible rationale for features of the D2 CoMFA contour map. Together these results suggest that CoMFA-homology based models may provide useful insights concerning differential agonist-receptor interactions at related receptors. The results also suggest that comparisons of CoMFA models for two structurally related receptors may be a fruitful approach for differential QSAR.