Feng Xixi, Sippel Claudia, Bracher Andreas, Hausch Felix
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry , Kraepelinstrasse 2, 80804 Munich, Germany.
Max Planck Institute of Biochemistry , Am Klopferspitz 18, 82152 Martinsried, Germany.
J Med Chem. 2015 Oct 8;58(19):7796-806. doi: 10.1021/acs.jmedchem.5b00785. Epub 2015 Sep 30.
The FK506-binding protein 51 (FKBP51) is a promising drug target for the treatment of stress-related psychiatric or metabolic disorders. Just recently, the first selective ligands for FKBP51 were reported based on an induced fit mechanism, but they are too large for a further drug development process. We therefore designed and synthesized a novel series of selective ligands to explore the requirements necessary for binding to the induced-fit conformation. All ligands of this series show no binding toward the structurally very similar antitarget FKBP52. With the cocrystal structure of the best ligand in this novel series we confirmed the induced fit mechanism. Furthermore, the structure-affinity relationship provides information about beneficial structural features, which is valuable for the development of improved FKBP51-directed drugs.
FK506结合蛋白51（FKBP51）是治疗应激相关精神或代谢紊乱的一个有前景的药物靶点。就在最近，基于诱导契合机制报道了首批FKBP51的选择性配体，但它们对于进一步的药物研发过程来说太大了。因此，我们设计并合成了一系列新型选择性配体，以探索与诱导契合构象结合所需的条件。该系列的所有配体对结构非常相似的反靶点FKBP52均无结合作用。通过该新型系列中最佳配体的共晶体结构，我们证实了诱导契合机制。此外，结构-亲和力关系提供了有关有益结构特征的信息，这对于开发改进的FKBP51导向药物很有价值。
