Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
J Med Chem. 2023 Oct 12;66(19):13556-13567. doi: 10.1021/acs.jmedchem.3c00852. Epub 2023 Sep 26.
The neuroprotective transcription factor Nurr1 was recently found to bind the dopamine metabolite 5,6-dihydroxyindole (DHI) providing access to Nurr1 ligand design from a natural template. We screened a custom set of 14 k extended DHI analogues in silico for optimized descendants to select 24 candidates for microscale synthesis and in vitro testing. Three out of six primary hits were validated as novel Nurr1 agonists with up to sub-micromolar binding affinity, highlighting the druggability of the Nurr1 surface region lining helix 12. In vitro profiling confirmed cellular target engagement of DHI descendants and demonstrated remarkable additive effects of combined Nurr1 agonist treatment, indicating diverse binding sites mediating Nurr1 activation, which may open new avenues in Nurr1 modulation.
最近发现神经保护转录因子 Nurr1 与多巴胺代谢物 5,6-二羟基吲哚（DHI）结合，为从天然模板设计 Nurr1 配体提供了途径。我们在计算机上筛选了一组定制的 14k 扩展 DHI 类似物，以寻找优化的后代，从中选择了 24 个候选物进行微尺度合成和体外测试。在六个主要命中中有三个被验证为新型 Nurr1 激动剂，其结合亲和力低至亚微米级，突出了 Nurr1 表面区域沿螺旋 12 排列的可药性。体外分析证实了 DHI 衍生物的细胞靶标结合，并证明了联合 Nurr1 激动剂治疗的显著附加效应，表明不同的结合位点介导 Nurr1 的激活，这可能为 Nurr1 调节开辟新途径。
