Revisiting silibinin as a novobiocin-like Hsp90 C-terminal inhibitor: Computational modeling and experimental validation

Food Chem Toxicol. 2019 Oct;132:110645. doi: 10.1016/j.fct.2019.110645. Epub 2019 Jun 26.


The flavonolignan silibinin is the major component of the extract isolated from the seeds of the milk thistle (Silybum marianum). Herein, we performed an in silico analysis focusing on the molecular docking of the putative atomic interactions between silibinin and heat shock protein 90 (Hsp90), an adenosine triphosphate-dependent molecular chaperone differentially expressed in response to microenvironmental stress. Time-resolved fluorescence resonance energy transfer was employed to measure the capacity of silibinin to inhibit Hsp90 binding to other co-chaperones with enzymatic activity. Whereas silibinin is predicted to interact with several pockets in the C-terminal domain (CTD) of Hsp90α and β, its highest-ranking docked poses significantly overlap with those of novobiocin, a well-characterized Hsp90 CTD-targeting inhibitor. The net biochemical effect of silibinin was to inhibit the efficiency of Hsp90α/β CTD binding to its co-chaperone PPID/cyclophilin D in the low millimolar range, equivalent to that observed for novobiocin. The hepatotoxicant behavior of silibinin solely occurred at concentrations several thousand times higher than those of the Hsp90 N-terminal inhibitor geldanamycin. Silibinin might be viewed as a non-hepatotoxic, novobiocin-like Hsp90 inhibitor that binds the CTD to induce changes in Hsp90 conformation and alter Hsp90-co-chaperone-client interactions, thereby providing new paths to developing safe and efficacious Hsp90 inhibitors.

Keywords: Cancer; Hsp90; Silibinin.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cyclophilins / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / chemistry
  • HSP90 Heat-Shock Proteins / metabolism*
  • Hep G2 Cells
  • Humans
  • Molecular Docking Simulation
  • Novobiocin / chemistry
  • Novobiocin / metabolism
  • Protein Binding
  • Protein Multimerization / drug effects
  • Silybin / chemistry
  • Silybin / metabolism*
  • Silybin / pharmacology*
  • Superoxides / metabolism


  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • HSP90AA2P protein, human
  • HSP90AB1 protein, human
  • Superoxides
  • Novobiocin
  • Silybin
  • Cyclophilins
  • PPID protein, human