Peltason Lisa, Bajorath Jürgen
Department of Life Science Informatics, B-IT, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstrasse 2, D-53113 Bonn, Germany.
Chem Biol. 2007 May;14(5):489-97. doi: 10.1016/j.chembiol.2007.03.011.
We systematically compare X-ray structures of inhibitor complexes of four well-known enzymes and correlate two- and three-dimensional (2D and 3D) similarity of inhibitors with their potency. The analysis reveals the presence of unexpected systematic relationships between molecular similarity and potency. These findings explain why apparently inconsistent structure-activity relationships (SARs) can coexist in different targets, and they have general implications for compound screening and optimization. The results suggest that (1) even for active sites with significant binding constraints, there is a high probability that structurally diverse ligands with similar activity can be identified, (2) different types of SARs are not mutually exclusive, and (3) the chemical nature of ligands is of comparable importance for SARs as the features of active sites. These insights aid in the understanding of target-specific SARs and their intrinsic degree of variability.
我们系统地比较了四种著名酶的抑制剂复合物的X射线结构，并将抑制剂的二维和三维（2D和3D）相似性与其效力相关联。分析揭示了分子相似性与效力之间存在意想不到的系统关系。这些发现解释了为什么明显不一致的构效关系（SARs）可以在不同靶点中共存，并且它们对化合物筛选和优化具有普遍意义。结果表明：（1）即使对于具有显著结合限制的活性位点，也很有可能识别出具有相似活性的结构多样的配体；（2）不同类型的SARs并非相互排斥；（3）配体的化学性质对于SARs与活性位点特征具有同等重要性。这些见解有助于理解靶点特异性SARs及其内在的可变程度。
