Zampieri Daniele, Mamolo Maria Grazia, Laurini Erik, Florio Chiara, Zanette Caterina, Fermeglia Maurizio, Posocco Paola, Paneni Maria Silvia, Pricl Sabrina, Vio Luciano
Department of Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
J Med Chem. 2009 Sep 10;52(17):5380-93. doi: 10.1021/jm900366z.
Novel benzo[d]oxazol-2(3H)-one derivatives were designed and synthesized, and their affinities against sigma receptors were evaluated. On the basis of 31 compounds, a three-dimensional pharmacophore model for the sigma(1) receptor binding site was developed using the Catalyst 4.9 software package. The best 3D pharmacophore hypothesis, consisting of one positive ionizable, one hydrogen bond acceptor, two hydrophobic aromatic, and one hydrophobic features provided a 3D-QSAR model with a correlation coefficient of 0.89. The best hypothesis was also validated by three independent methods, i.e., the Fisher randomization test included in the CatScramble functionality of Catalyst, the leave-one-out test, and activity prediction of an additional test set. The achieved results will allow researchers to use this 3D pharmacophore model for the design and synthesis of a second generation of high affinity sigma(1) ligands, as well as to discover other lead compounds for this class of receptors.
设计并合成了新型苯并[d]恶唑-2(3H)-酮衍生物，并评估了它们与σ受体的亲和力。基于31种化合物，使用Catalyst 4.9软件包开发了用于σ(1)受体结合位点的三维药效团模型。最佳的三维药效团假设由一个可电离正离子、一个氢键受体、两个疏水芳香基团和一个疏水特征组成，提供了一个相关系数为0.89的三维定量构效关系模型。该最佳假设还通过三种独立方法进行了验证，即Catalyst的CatScramble功能中包含的Fisher随机化检验、留一法检验以及额外测试集的活性预测。所取得的结果将使研究人员能够使用这个三维药效团模型来设计和合成第二代高亲和力σ(1)配体，以及发现这类受体其他的先导化合物。
