Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
Mol Divers. 2014 Feb;18(1):149-59. doi: 10.1007/s11030-013-9483-5. Epub 2013 Oct 1.
The binding modes of 42 oxadiazole derivates inside glycogen synthase kinase 3 beta (GSK3β were determined using docking experiments; thus, the preferred active conformations of these inhibitors are proposed. We found that these compounds adopt a scorpion-shaped conformation and they accept a hydrogen bond (HB) from the residue Val135 of the GSK3β ATP-binding site hinge region. In addition, quantitative structure-activity relationship (QSAR) models were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. In a first approach, three-dimensional (3D) vectors were calculated using docking conformations and, by using multiple-linear regression, we assessed that GETAWAY vectors were able to describe the reported biological activities. In other QSAR approach, SMILES-based optimal descriptors were calculated. The best model included three-SMILES elements SSSβ leading to the identification of key molecular features that contribute to a high GSK3β inhibitory activity.
使用对接实验确定了 42 种恶二唑衍生物在糖原合酶激酶 3β（GSK3β）内的结合模式；因此，提出了这些抑制剂的优选活性构象。我们发现这些化合物采用了蝎子形状的构象，并且它们接受来自 GSK3β ATP 结合位点铰链区域残基 Val135 的氢键 (HB)。此外，还构建了定量构效关系 (QSAR) 模型，以解释所研究化合物对 GSK3β 抑制活性的趋势。在第一种方法中，使用对接构象计算了三维 (3D) 向量，并且通过多元线性回归，我们评估了 GETAWAY 向量能够描述报道的生物学活性。在另一种 QSAR 方法中，计算了基于 SMILES 的最佳描述符。最佳模型包括三个 SMILES 元素 SSSβ，从而确定了有助于高 GSK3β 抑制活性的关键分子特征。
