Jöst Christian, Nitsche Christoph, Scholz Therese, Roux Lionel, Klein Christian D
Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University , Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
J Med Chem. 2014 Sep 25;57(18):7590-9. doi: 10.1021/jm5006918. Epub 2014 Sep 5.
Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
共价配体-靶点相互作用具有显著的药理学优势。然而，通常具有亲电性质的反应基团的脱靶反应性必须降至最低，并且不可逆抑制剂的选择性是一项关键要求。因此，我们进行了一项系统研究，以确定几种可用作共价结合配体构建模块的亲电基团的选择性。将六个具有调节亲电性的反应基团与11个非反应性部分相结合，得到了一个由72种类片段化合物组成的小型组合文库。针对一组11种酶靶点对这些化合物进行筛选，以评估它们的选择性以及与蛋白质发生混杂结合的可能性。测定结果表明，即使对于筛选集中那些含有据称具有高反应活性亲电试剂的成员，混杂程度也比最初预期的要低得多。
