Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Friedrich-Hirzebruch-Allee 6, D-53115 Bonn, Germany.
J Med Chem. 2022 Jan 27;65(2):922-934. doi: 10.1021/acs.jmedchem.0c02076. Epub 2021 Jan 21.
Allosteric kinase inhibitors are thought to have high selectivity and are prime candidates for kinase drug discovery. In addition, the exploration of allosteric mechanisms represents an attractive topic for basic research and drug design. Although the identification and characterization of allosteric kinase inhibitors is still far from being routine, X-ray structures of kinase complexes have been determined for a significant number of such inhibitors. On the basis of structural data, allosteric inhibitors can be confirmed. We report a comprehensive survey of allosteric kinase inhibitors and activators from publicly available X-ray structures, map their binding sites, and determine their distribution over binding pockets in kinases. In addition, we discuss structural features of these compounds and identify active structural analogues and high-confidence target annotations, indicating additional activities for a subset of allosteric inhibitors. This contribution aims to provide a detailed structure-based view of allosteric kinase inhibition.
变构激酶抑制剂被认为具有高选择性，是激酶药物发现的首选候选药物。此外，变构机制的探索代表了基础研究和药物设计的一个有吸引力的课题。尽管变构激酶抑制剂的鉴定和表征还远未成为常规操作，但已经确定了大量此类抑制剂的激酶复合物的 X 射线结构。基于结构数据，可以确认变构抑制剂。我们报告了对来自公开 X 射线结构的变构激酶抑制剂和激活剂的全面调查，绘制了它们的结合位点，并确定了它们在激酶结合口袋中的分布。此外，我们讨论了这些化合物的结构特征，并确定了活性结构类似物和高可信度的靶标注释，这表明了一部分变构抑制剂的额外活性。本研究旨在提供变构激酶抑制的详细基于结构的观点。
