Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies.
Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previous study, the presence of the farnesyl group in the structure of 2-arylbenzofurans was found to have positive influences on their pancreatic lipase inhibitory activity. In the present study, we have confirmed the authenticity of the notation based on the PTP1B inhibitory activity of farnesylated 2-arylbenzofurans. Specifically, two farnesylated 2-arylbenzofurans [morusalfurans B (2) and C (3)] showed strong inhibitory effects on PTP1B with IC50 values of 8.92 and 7.26 µM, respectively, which was significantly higher than that of the positive controls [sodium orthovanadate (IC50 = 15.10 µM) and ursolic acid (IC50 = 11.34 µM)]. Besides, two 2-arylbenzofurans [morusalfurans A (1) and F (6)], one flavonoid [morusalnol B (9)], and one geranylated stilbene [morusibene A (11)] exhibited PTP1B inhibition with IC50 values ranging from 11.02 to 26.56 µM. Kinetic studies revealed compounds 2, 3, 6, and 11 as mixed type PTP1B inhibitors, while 1 and 9 are known as noncompetitive. Molecular docking simulations demonstrated that these active compounds can bind with the respective catalytic or/and allosteric sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. To the best of our knowledge, this is the first time, the PTP1B inhibitory activity of eleven compounds (1-11), as well as the mechanism of action underlying the effects on PTP1B enzyme of the active compounds, were investigated. In vitro and in silico results suggest that the farnesylated 2-arylbenzofurans from M. alba may potentially be utilized as an effective treatment therapy for type 2 diabetes mellitus and its associated complications.
['Ha|Manh Tuan|MT|', 'Shrestha|Srijan|S|', 'Tran|Thu Huong|TH|', 'Kim|Jeong Ah|JA|', 'Woo|Mi Hee|MH|', 'Choi|Jae Sue|JS|', 'Min|Byung Sun|BS|http://orcid.org/0000-0002-8501-4289']
D000494:Allosteric Regulation D001572:Benzofurans D020134:Catalytic Domain D003924:Diabetes Mellitus, Type 2 D057075:Enzyme Assays D006801:Humans D007004:Hypoglycemic Agents D020128:Inhibitory Concentration 50 D007328:Insulin D007700:Kinetics D062105:Molecular Docking Simulation D031625:Morus D024301:Plant Bark D010936:Plant Extracts D018517:Plant Roots D054876:Prenylation D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
Farnesylated 2-arylbenzofurans Morus alba Protein tyrosine phosphatase 1B Kinetic Molecular docking Moraceae