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Profiling Withanolide A for Therapeutic Targets in Neurodegenerative Diseases

Profiling Withanolide A for Therapeutic Targets in Neurodegenerative Diseases

Erika A Crane, Wolfgang Heydenreuter, Katharina R Beck, Petra Strajhar, Jan Vomacka, Martin Smiesko, Elma Mons, Lydia Barth, Markus Neuburger, Angelo Vedani, Alex Odermatt, Stephan A Sieber, Karl Gademann

Bioorg Med Chem. 2019 Jun 15;27(12):2508-2520.

PMID: 30929949

Abstract:

To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-κB, TRα, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP32911629	Withanolide A		32911-62-9	Price

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