α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme’s activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure–activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG.

α-Glucosidase inhibition by flavonoids: an in vitro and in silico structure-activity relationship study.

Polyphenols, as one group of secondary metabolite, are widely distributed in plants and have been reported to show various bioactivities in recent year. Starch digestion not only is related with food industrial applications such as brewing but also plays an important role in postprandial blood glucose level, and therefore insulin resistance. Many studies have shown that dietary phenolic extracts and pure polyphenols can retard starch digestion in vitro, and the retarding effect depends on the phenolic composition and molecular structure. Besides, dietary polyphenols have also been reported to alleviate elevation of blood glucose level after meal, indicating the inhibition of starch digestion in vivo. This review aims to analyze how dietary polyphenols affect starch digestion both in vitro and in vivo. We can conclude that the retarded starch digestion in vitro by polyphenols results from inhibition of key digestive enzymes, including α-amylase and α-glucosidase, as well as from interactions between polyphenols and starch. The alleviation of postprandial hyperglycemia by polyphenols might be caused by both the inhibited starch digestion in vivo and the influenced glucose transport. Therefore, phenolic extracts or pure polyphenols may be alternatives for preventing and treating type II diabetes disease.

Dietary polyphenols modulate starch digestion and glycaemic level: a review.

Uric acid is the final oxidation product of purine metabolism in humans. Xanthine oxidoreductase (XOR) catalyzes oxidative hydroxylation of hypoxanthine to xanthine to uric acid, accompanying the production of reactive oxygen species (ROS). Uric acid usually forms ions and salts known as urates and acid urates in serum. Clinically, overproduction or under-excretion of uric acid results in the elevated level of serum uric acid (SUA), termed hyperuricemia, which has long been established as the major etiologic factor in gout. Accordingly, urate-lowering drugs such as allopurinol, an XOR-inhibitor, are extensively used for the treatment of gout. In recent years, the prevalence of hyperuricemia has significantly increased and more clinical investigations have confirmed that hyperuricemia is an independent risk factor for cardiovascular disease, hypertension, diabetes, and many other diseases. Urate-lowering therapy may also play a critical role in the management of these diseases. However, current XOR-inhibitor drugs such as allopurinol and febuxostat may have significant adverse effects. Therefore, there has been great effort to develop new XOR-inhibitor drugs with less or no toxicity for the long-term treatment or prevention of these hyperuricemia-related diseases. In this review, we discuss the mechanism of uric acid homeostasis and alterations, updated prevalence, therapeutic outcomes, and molecular pathophysiology of hyperuricemia-related diseases. We also summarize current discoveries in the development of new XOR inhibitors.

Hyperuricemia-Related Diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview

Inhibition mechanism of ferulic acid against α-amylase and α-glucosidase

Inhibitory effect of phloretin on α-glucosidase: Kinetics, interaction mechanism and molecular docking.

Inhibition of α-glucosidase activity may suppress postprandial hyperglycemia. The inhibition kinetic analysis showed that apigenin reversibly inhibited α-glucosidase activity with an IC50 value of (10.5 ± 0.05) × 10–6 mol L–1, and the inhibition was in a noncompetitive manner through a monophasic kinetic process. The fluorescence quenching and conformational changes determined by fluorescence and circular dichroism were due to the formation of an α-glucosidase–apigenin complex, and the binding was mainly driven by hydrophobic interactions and hydrogen bonding. The molecular simulation showed that apigenin bound to a site close to the active site of α-glucosidase, which may induce the channel closure to prevent the access of substrate, eventually leading to the inhibition of α-glucosidase. Isobolographic analysis of the interaction between myricetin and apigenin or morin showed that both of them exhibited synergistic effects at low concentrations and tended to exhibit additive or antagonistic interaction a...

Inhibitory Mechanism of Apigenin on α-Glucosidase and Synergy Analysis of Flavonoids.

The flavonoid family has been reported to possess a high potential for inhibition of xanthine oxidase (XO). This study concerned the structural aspects of inhibitory activities and binding affinities of flavonoids as XO inhibitors. The result indicated that the hydrophobic interaction was important in the binding of flavonoids to XO, and the XO inhibitory ability increased generally with increasing affinities within the class of flavones and flavonols. The planar structure and the C2═C3 double bonds of flavonoids were advantageous for binding to XO and for XO inhibition. Both the hydroxylation on ring B and the substitution at C3 were unfavorable for XO inhibition more profoundly than their XO affinity. The methylation greatly reduced the inhibition (0.75–3.07 times) but hardly affected the affinity. The bulky sugar substitutions of flavonoids decreased the inhibition (1.69–1.99 times) and lowered the affinities (4.20–9.22 times) to different degrees depending on the conjunction site.

Dietary Flavonoids as Xanthine Oxidase Inhibitors: Structure-Affinity and Structure-Activity Relationships.

Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism

Genistein (Gen), widely distributed in soybean, is proved to be important in homeostasis in the human body. Herein, the inhibitory mechanism of Gen against xanthine oxidase (XO) was studied through multispectroscopic methods and molecular simulation. The inhibition kinetics showed that Gen competitively inhibited XO with an inhibition constant of (1.39 ± 0.11) μM by competing with xanthine for binding to the active site of XO. Fluorescence titration study suggested that the fluorescence quenching mechanism of XO was static, resulting from the formation of a Gen-XO complex at one fold site. The calculated thermodynamic parameters revealed that the interaction process was driven mainly by hydrophobic interactions and hydrogen bonds with affinity of (5.24 ± 0.02) × 10(4) Lmol(-1). Conformational analyses demonstrated that the microenvironment and the secondary structure of XO were changed upon binding of Gen. The molecular docking displayed that Gen bound to the active cavity of XO by interacting with the surrounding amino acid residues (Leu648, Phe649, Glu802, Ser876, Glu879, Arg880, Phe914, Phe1009, Thr1010 and Phe1013). Thus, the inhibition may be attributed to the insertion of Gen into the active site of XO occupying the catalytic center of the enzyme to avoid entry of the substrate and inducing conformational changes of XO (more compact), which was further unfavorable for forming the active cavity and further reduced the landing and oxidation of substrate. This study may offer novel insights into the inhibition mechanism of Gen on XO.

Suyun Lin

Papers

Inhibitory Mechanism of Apigenin on α-Glucosidase and Synergy Analysis of Flavonoids.

Dietary Flavonoids as Xanthine Oxidase Inhibitors: Structure-Affinity and Structure-Activity Relationships.

Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism

Deciphering the inhibitory mechanism of genistein on xanthine oxidase in vitro.

Synthesis, characterization and xanthine oxidase inhibition of Cu(II)–chrysin complex