Profiling withanolide A for therapeutic targets in neurodegenerative diseases

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

doi:10.5167/uzh-196514

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Crane, E. A., Heydenreuter, W., Beck, K. R., Strajhar, P., Vomacka, J., Smiesko, M., Mons, E., Barth, L., Neuburger, M., Vedani, A., Odermatt, A., Sieber, S. A., & Gademann, K. (2019). Profiling withanolide A for therapeutic targets in neurodegenerative diseases. Bioorganic & Medicinal Chemistry, 27, 2508–2520. https://doi.org/10.1016/j.bmc.2019.03.022

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 neuroblastom