Hasegawa Kiyoshi, Arakawa Masamoto, Funatsu Kimito
Nippon Roche Research Center, Kajiwara, Kamakura, 247-8530, Japan.
Comput Biol Chem. 2003 Jul;27(3):211-6. doi: 10.1016/s0097-8485(02)00055-4.
In this study, we propose a new three-dimensional quantitative structure-activity relationship (3D-QSAR) method for selecting bioactive conformations and alignment rule simultaneously. The possible conformations of all molecules are generated by conformational analysis and they are superimposed on template conformer with possible alignment rules. The field variables are calculated as 3D descriptor of structures. Four-way partial least-squares (PLS) analysis is applied, and the conformations and alignment rule largely contributing to biological activity are selected. In order to demonstrate this method, the data set of benzodiazepine derivatives, antagonists of (CCK-B), was used as a test sample. As a result, appropriate conformers and alignment rule were selected and significant PLS model was obtained. The resulting final model could give the reasonable 3D coefficient contour maps. Moreover, external prediction was carried out by use of external data sample and its prediction was proved to be high enough.
在本研究中，我们提出了一种新的三维定量构效关系（3D-QSAR）方法，可同时选择生物活性构象和比对规则。所有分子的可能构象通过构象分析生成，并按照可能的比对规则与模板构象进行叠加。场变量作为结构的三维描述符进行计算。应用四元偏最小二乘法（PLS）分析，选择对生物活性有很大贡献的构象和比对规则。为了验证该方法，使用苯二氮䓬衍生物数据集（CCK-B拮抗剂）作为测试样本。结果，选择了合适的构象和比对规则，并获得了显著的PLS模型。最终得到的模型能够给出合理的三维系数等高线图。此外，利用外部数据样本进行了外部预测，结果证明其预测能力足够高。
