Boström Jonas, Hogner Anders, Schmitt Stefan
Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden.
J Med Chem. 2006 Nov 16;49(23):6716-25. doi: 10.1021/jm060167o.
The scope of the current work is to investigate whether structurally similar ligands bind in a similar fashion by exhaustively analyzing experimental data from the protein database (PDB). The complete PDB was searched for pairs of structurally similar ligands binding to the same biological target. The binding sites of the pairs of proteins complexing structurally similar ligands were found to differ in 83% of the cases. The most recurrent structural change among the pairs involves different water molecule architecture. Side-chain movements are observed in half of the pairs, whereas backbone movements rarely occurred. However, two structurally similar ligands generally confirm a high degree of structural conservation. That is, a majority of the ligand pairs occupy the same region in the binding sites, providing support for the use of shape matching in the drug design process. We allow ourselves to draw general conclusions because our data set consists of ligands with drug-like physicochemical properties complexed to a broad spectrum of different protein classes.
当前工作的范围是通过详尽分析来自蛋白质数据库（PDB）的实验数据，研究结构相似的配体是否以相似的方式结合。在完整的PDB中搜索与同一生物靶点结合的结构相似的配体对。发现83%的情况下，结合结构相似配体的蛋白质对的结合位点存在差异。这些蛋白质对中最常见的结构变化涉及不同的水分子结构。在一半的蛋白质对中观察到侧链移动，而主链移动很少发生。然而，两个结构相似的配体通常具有高度的结构保守性。也就是说，大多数配体对占据结合位点中的相同区域，这为在药物设计过程中使用形状匹配提供了支持。我们能够得出一般性结论，因为我们的数据集包含具有类药物理化性质的配体，它们与广泛的不同蛋白质类别形成复合物。
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