Structure activity related, mechanistic, and modeling studies of gallotannins containing a glucitol-core and α-glucosidase

Abstract

Gallotannins containing a glucitol core, which are only produced by members of the maple (Acer) genus, are more potent α-glucosidase inhibitors than the clinical drug, acarbose. While this activity is influenced by the number of substituents on the glucitol core (e.g. more galloyl groups leads to increased activity), the mechanisms of inhibitory action are not known. Herein, we investigated ligand-enzyme interactions and binding mechanisms of a series of ‘glucitol-core containing gallotannins (GCGs)’ against the α-glucosidase enzyme. The GCGs included ginnalins A, B and C (containing two, one, and one galloyl/s, respectively), maplexin F (containing 3 galloyls) and maplexin J (containing 4 galloyls). All of the GCGs were noncompetitive inhibitors of α-glucosidase and their interactions with the enzyme were further explored using biophysical and spectroscopic measurements. Thermodynamic parameters (by isothermal titration calorimetry) revealed a 1:1 binding ratio between GCGs and α-glucosidase. The binding regions between the GCGs and α-glucosidase, probed by a fluorescent tag, 1,1′-bis(4-anilino-5-napththalenesulfonic acid, revealed that the GCGs decreased the hydrophobic surface of the enzyme. In addition, circular dichroism analyses showed that the GCGs bind to α-glucosidase and lead to loss of the secondary α-helix structure of the protein. Also, molecular modeling was used to predict the binding site between the GCGs and the α-glucosidase enzyme. This is the first study to evaluate the mechanisms of inhibitory activities of gallotannins containing a glucitol core on α-glucosidase.

Experimental and computational characterization on the binding of two fluoroquinolones to bovine hemoglobin

“…The data fit well with the sum of single exponential decays with χ 2 values close to 1.00. As shown in Figure , the fluorescence lifetime of BHb presents no obvious changes under different concentrations of both CPFX and ENFX, which confirms that the quenching mode of BHb fluorescence caused by 2 FQs could be attributed to the static one, meaning the formation of the FQ − BHb complex …”

Antihyperglycemic, antioxidant activities of two Acer palmatum cultivars, and identification of phenolics profile by UPLC-QTOF-MS/MS: New natural sources of functional constituents

“…The outstanding activity against ␣-glucosidase could be due to the presence of tannins and flavonoids since hydrolysable tannins and flavonoids generally show effective inhibition on ␣-glucosidase activity (Li et al, 2009; Ma et al, 2015;Zhang et al, 2015b). Li and colleagues found that vitexin and isovitexin were the major ␣-glucosidase inhibitors in Hawthorn leaves, which indicated stronger inhibition than acarbose with the IC 50 value of 25.11, 23.26 and 228.16 M, respectively (Li et al, 2009).…”

“…However, synthetic inhibitors, such as acarbose and miglitol, have serious undesirable adverse effects, such as flatulence, diarrhea and serious hepatitis (Carrascosa et al, 1997;Diaz-Gutierrez et al, 1998). At this point, effective, non-toxic and inexpensive ␣-glucosidase inhibitors derived from plant sources were reported to be more acceptable to consumers, and the significance is increasing all over the world (Kalra, 2014;Ma et al, 2015;Zhang et al, 2016).…”

“…Attractively, a series of novel compounds, such as maplexin A-F, have been isolated and identified by means of chromatography techniques and elucidation of NMR and ESIMS data . Meanwhile, maple extracts were evidenced to show good antiproliferative (González-Sarrías et al, 2012a,b), antiinflammatory (Nahar et al, 2014), anticancer (González-Sarrías et al, 2013), antihyperglycemic (Apostolidis et al, 2012), and antioxidant activities (Zhang et al, 2015b), especially the potential in preventing diabetes and diabetic complications (Apostolidis et al, 2012;Ma et al, 2015).…”

Glucitol-core containing gallotannins inhibit the formation of advanced glycation end-products mediated by their antioxidant potential

“…27,28 Maplexin J (MJ; contains 4 galloyls) was synthesized in our laboratory as previously reported. 39 The structures of the GCGs are shown in Figure 1.…”