Low Caroline M R, Vinter J G
James Black Foundation, London, UK.
J Med Chem. 2008 Feb 14;51(3):565-73. doi: 10.1021/jm070880t. Epub 2008 Jan 18.
Cholecystokinin 2 receptor antagonists encompass a wide range of structures. This makes them unsuitable candidates for existing 3D-QSAR methods and has led us to develop an alternative approach to account for their observed biological activities. A diverse set of 21 antagonists was subjected to a novel molecular field-based similarity analysis. The hypothesis is that compounds with similar field patterns will bind at the same target site regardless of their underlying structure. This initial report demonstrates a linear correlation between ligand similarity and biological activity for this challenging data set. A model generated with three molecules was used to predict the activity of 18 test compounds, with different chemotypes, with a root-mean-square error of 0.68 pKB units. The ability to automatically derive a molecular alignment without knowledge of the protein structure represents an improvement over existing pharmacophore methods and makes the method particularly suitable for scaffold-hopping.
胆囊收缩素2受体拮抗剂具有广泛的结构。这使得它们不适用于现有的三维定量构效关系方法，因此我们开发了一种替代方法来解释它们所观察到的生物活性。对一组多样的21种拮抗剂进行了基于新型分子场的相似性分析。其假设是，具有相似场模式的化合物，无论其基础结构如何，都会在相同的靶位点结合。这份初步报告证明了对于这个具有挑战性的数据集，配体相似性与生物活性之间存在线性相关性。用三个分子生成的模型被用于预测18种具有不同化学类型的测试化合物的活性，均方根误差为0.68 pKB单位。在无需了解蛋白质结构的情况下自动得出分子比对的能力代表了相对于现有药效团方法的一种改进，并且使得该方法特别适用于骨架跃迁。
