Analysis of glycyrrhizin binding to protein HMGB1

Abstract

Glycyrrhizin (GLR) is triterpenoid saponin used for the treatment of various of liver and skin diseases. GLR blocks the nucleocytoplasmic translocation of the protein HMGB1, thereby inhibiting its extracellular release and its functions as a damage-associated molecular pattern molecule. Here we have analyzed the interaction with HMGB1 of GLR and its three main metabolites mono-glucuronyl-glycyrrhetinic acid (MGA), glycyrrhetinic acid (GA) and a sulfate metabolite of GA (Cpd 3). We determined the optimized binding configurations (starting from crystallographic data for HMGB1) of the bound 18α- and 18β-epimers to compare the potential energy of interaction (ΔE) and free energy of hydration (ΔG). The molecular modeling shows that GLR and MGA can form much more stable complexes with HMGB1 than the non-glycosylated molecules GA and Cpd 3. The glucuronic acid residue common to GLR and MGA directly attached to the terpenoid core contributes importantly to the protein interaction. 18α-GLR (isoglycyrrhizinate) appeared as a better binder to HMG Box B than 18β-GLR, whereas both epimers bind very well to HMG Box A. The stabilization of HMG Box A through an intramolecular cystine disulfide bond further increases the stability of the GLR-HMG Box A complexes. On the opposite GA and Cpd 3 exhibit a considerably weaker HMG binding capacity. The study provides a detailed in silico analysis of the interaction of GLR with HMGB1; the limitations and biological implications are discussed.

Keywords

• Glycyrrhizin
• HMGB1
• drug-protein binding
• molecular modelling
• cancer