ABSTRACT
CONTEXT: Anoectochilus chapaensis Gagnep. (Orchidaceae), an indigenous and valuable Chinese folk medicine, has been used as an antidiabetic remedy. However, the bioactive constituents have not been reported. OBJECTIVE: To explore potent protein tyrosine phosphatase 1B (PTP1B) inhibitors from the whole herbs of A. chapaensis for the treatment of diabetes. MATERIALS AND METHODS: The compounds were obtained by PTP1B bioactivity-guided isolation from the active fraction of ethonal extract of A. chapaensis, and elucidated by extensive spectroscopic methods and evaluated for their potential to inhibit PTP1B with a series of doses in dimethyl sulphoxide by a colorimetric assay in vitro. The Autodock program was used to dock the active compounds into the binding sites. RESULTS: Fifteen compounds were identified; epifriedelanol, friedelane, 2α, 3ß-dihydroxyolean-12-en-23, 28, 30-trioic acid, dibutyl-phthalate, and 7-hydroxy-2-methoxy-9,10-dihydrophenanthrene-1,4-dione were isolated from the genera Anoectochilus for the first time. All 15 compounds were tested for their inhibitory activity against PTP1B in vitro. Nine active compounds exhibited potent inhibitory effect with IC50 values of 1.16-6.21 µM, which were comparable with the positive control suramin. The 3D-docking simulations showed negative binding energies of -7.4 to -8.5 kcal/mol and supported a high affinity to PTP1B residues in the pocket site, indicating that they may stabilize the open form and generate tighter binding to the catalytic sites of PTP1B. DISCUSSION AND CONCLUSION: The results clearly demonstrated that the potential active constituents from A. chapaensis could inhibit PTP1B, which may be mainly attributed to a combination of triterpenoids and flavonoids.
Subject(s)
Drugs, Chinese Herbal/metabolism , Drugs, Chinese Herbal/pharmacology , Orchidaceae , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Binding Sites/drug effects , Binding Sites/physiology , Drugs, Chinese Herbal/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Protein Structure, Secondary , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Structure-Activity RelationshipABSTRACT
OBJECTIVE: Our goal in this study aims to explain the polypharmacological mechanism at the molecular level responsible for the effectiveness of a traditional Chinese medicine (TCM) prescription FTZ to treat hyperlipidemia and related disease. DESIGN: By MDL(®) ISIS_Base 2.5, we constructed a compound database based on the FTZ constituents, which were detected in the rat serum after oral administration of the TCM through ultra-performance liquid chromatography/quadruple-time-of-flight mass-spectrometry (UPLC/Q-TOF-MS/MS) method. After validation of the virtual docking system, we used molecular screening by LigandFit which is a computational method for the shape-directed rapid docking of ligands to target protein active sites, to investigate the interactions between the components in database and lipid-modulating targets in the liver. RESULTS: In the prescription FTZ ingredients, there were sixteen constituents including jatrorrhizine, etc. showed potential effects towards the hyperlipidemia-related targets: HMG-CoA reductase (HMGR), squalene synthase (SQS), oxidosqualene cyclase (OSC), cholesteryl ester transfer protein (CETP), liver X receptor (LXR), farnesoid X receptor (FXR) and peroxisome proliferator-activated receptors (PPARα and PPARγ). Among the eight herbs in prescription FTZ, Rhizoma Coptidis (RC) plays the most important role in whole effect from FTZ on hyperlipidemia related disease. CONCLUSIONS: Our research demonstrated that Chinese medicine formula FTZ has multi-target synergistic effect on hyperlipidemia and suggests the pharmacodynamic material basis could be jatrorrhizine, berberrubine, berberine and salidroside.
