Profiling withanolide A for therapeutic targets in neurodegenerative diseases. Issue 12 (15th June 2019)

• Record Type: Journal Article
• Authors: Crane, Erika A.; Heydenreuter, Wolfgang; Beck, Katharina R.; Strajhar, Petra; Vomacka, Jan; Smiesko, Martin; Mons, Elma; Barth, Lydia; Neuburger, Markus; Vedani, Angelo; Odermatt, Alex; Sieber, Stephan A.; Gademann, Karl
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 12(2019)
• Page Start: 2508
• Page End: 2520
• Publication Date: 2019-06-15
• Subjects: GR glucocorticoid receptor, NR3C1 -- WitA withanolide A -- Dex Dexamethasone -- Mife mifepristone, RU-486, RU38486 -- ATRA or RA all-trans retinoic acid -- DMSO dimethyl sulfoxide -- BACE1 beta-secretase 1 -- ADAM10 a disintegrin and metalloproteinase domain-containing protein 10 -- SAR structure-activity relationship -- QSAR quantitative structure-activity relationship -- SILAC stable isotope labeling of amino acids in cell culture -- MR mineralocorticoid receptor -- Akt protein kinase B, PKB -- ERK1/2 extracellular regulated kinase 1/2 -- NGF nerve growth factor -- HD Huntington's disease -- AD Alzheimer's disease -- PD Parkinson's disease -- GC glucocorticoid -- ABPP activity-based protein profiling -- NGF nerve growth factor -- Cort cortisol -- Aldo aldosterone -- Spiro spironolactone -- H-bonding hydrogen bonding; Withanolide A -- Target profiling -- Glucocorticoid receptor -- Neurotrophic agents; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.03.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.