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

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