201. Characterization of the inhibitory activity of natural tanshinones from Salvia miltiorrhiza roots on protein tyrosine phosphatase 1B
- Author
-
Ting Yu, Hyun Ah Jung, Da Hye Kim, Takako Yokozawa, Pradeep Paudel, Thi Men Ngo, Jeong Ah Kim, and Jae Sue Choi
- Subjects
0301 basic medicine ,Salvia miltiorrhiza ,Pharmacology ,Toxicology ,Inhibitory postsynaptic potential ,Plant Roots ,01 natural sciences ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Allosteric Regulation ,Catalytic Domain ,Enzyme Inhibitors ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,chemistry.chemical_classification ,Binding Sites ,biology ,Active site ,General Medicine ,AutoDock ,biology.organism_classification ,0104 chemical sciences ,Molecular Docking Simulation ,Ferruginol ,Kinetics ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Enzyme ,chemistry ,Abietanes ,biology.protein ,Thermodynamics ,Lamiaceae ,Signal transduction - Abstract
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator that plays an important role in many signaling pathways, especially those associated with insulin resistance. In this study, we investigated the anti-diabetic potential of 12 natural tanshinones isolated from Salvia miltiorrhiza (S. miltiorrhiza) Bunge (Lamiaceae), deoxyneocryptotanshinone (1), grandifolia F (2), ferruginol (3), cryptotanshinone (4), tanshinone IIA (5), tanshinol B (6), tanshinone IIB (7), tanshinonal (8), methyl tanshinonate (9), 15,16-dihydrotanshinone I (10), tanshinone I (11), and dehydrodanshenol A (12) and evaluated their inhibitory activity against PTP1B. Tanshinones 4, 6 and 12 exhibited potent PTP1B inhibitory activity with IC50 values of 5.5 ± 0.9, 4.7 ± 0.4 and 8.5 ± 0.5 μM, respectively. In addition, tanshinones 1–3, 5 and 7–11 showed promising dose-dependent inhibition of PTP1B over IC50 values ranging from 18.6 to 254.8 μM. Enzyme kinetic analysis of PTP1B inhibition revealed that 4 and 6 were mixed -noncompetitive type inhibitors, whereas 12 was a classical-noncompetitive type inhibitor. Furthermore, 4, 6 and 12 were docked with the PTP1B enzyme using molecular docking simulations (AutoDock 4.2) and exhibited negative binding energy (−6.4 to −8.7 kcal/mol), indicating high binding affinity to PTP1B active site residues. Structure-activity relationships (SAR) analysis revealed that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influenced their activity. Overall, results indicated that tanshinones from S. miltiorrhiza are potential anti-diabetic candidates that should be explored in the development of preventive and therapeutic modalities for the treatment of diabetes as well as diabetes-associated complications.
- Published
- 2017