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Structure-Guided Design of Nurr1 Agonists Derived from the Natural Ligand Dihydroxyindole.

ABSTRACT: 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.

SUBMITTER: Sai M

PROVIDER: S-EPMC10578347 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Structure-Guided Design of Nurr1 Agonists Derived from the Natural Ligand Dihydroxyindole.

Sai Minh M Vietor Jan J Kornmayer Moritz M Egner Markus M López-García Úrsula Ú Höfner Georg G Pabel Jörg J Marschner Julian A JA Wein Thomas T Merk Daniel D

Journal of medicinal chemistry 20230926 19

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 th ...[more]

PMID: 37751901

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