Schnur Dora M, Hermsmeier Mark A, Tebben Andrew J
Computer Aided Drug Design and Lead Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA.
J Med Chem. 2006 Mar 23;49(6):2000-9. doi: 10.1021/jm0502900.
One of the early and effective approaches to G-coupled protein receptor target family library design was the analysis of a set of ligands for frequently occurring chemical moieties or substructures. Various methods ranging from frameworks analysis to pharmacophores have been employed to find these so-called target-family-privileged substructures. Although the use of these substructures is common practice in combinatorial library design and has produced leads, the methods used for finding them rarely verified their selectivity for the particular target family from which they were derived. The frequency of occurrence among ligands associated with a target receptor family is not a sufficient criterion for those substructures to receive the label of target-family-privileged substructure. This study explores the question of selectivity of ClassPharmer generated fragments for a series of target families: GPCRs, nuclear hormone receptors, serine proteases, protein kinases, and ligand-gated ion channels. In addition, a GPCR focused library and a random set of 10k compounds are examined in terms of their target-family-privileged-substructure composition. The results challenge the combinatorial chemistry concept of target-family-privileged substructures and suggest that many of these fragments may simply be drug-like or attractive for various receptors in accordance with the original definition of privileged substructures.
G 蛋白偶联受体靶标家族文库设计的早期有效方法之一是分析一组配体中常见的化学基团或子结构。从骨架分析到药效团等各种方法都被用于寻找这些所谓的靶标家族特有的子结构。尽管在组合文库设计中使用这些子结构是常见做法并且已经产生了先导化合物，但用于寻找它们的方法很少验证其对特定靶标家族的选择性，而这些子结构正是从该靶标家族衍生而来的。与靶标受体家族相关的配体中出现的频率并不是这些子结构获得靶标家族特有的子结构这一标签的充分标准。本研究探讨了 ClassPharmer 生成的片段对一系列靶标家族（G 蛋白偶联受体、核激素受体、丝氨酸蛋白酶、蛋白激酶和配体门控离子通道）的选择性问题。此外，还从其靶标家族特有的子结构组成方面研究了一个聚焦于 G 蛋白偶联受体的文库和一组 10k 随机化合物。结果对靶标家族特有的子结构的组合化学概念提出了挑战，并表明根据特权子结构的原始定义，这些片段中的许多可能仅仅是类药物的或对各种受体具有吸引力。
