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QSAR study of flavonoids as inhibitors of a- glucosidase

Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in insulin secretion and/or by decreased responsiveness of the organs to secreted insulin. Such a deficiency results in increased blood glucose levels than in turn can damage many of the body's systems, including blood vessels and nerves. Small intestinal a- glucosidase and pancreatic a-amylase are key enzymes of dietary carbohydrate digestion in humans. Inhibitors of these enzymes may be effective in retarding carbohydrate digestion and glucose absorption to suppress postprandial hyperglycaemia. Postprandial glucose levels impact on serum levels of glycosylated haemoglobin (HbA1c), an established risk indicator for microvascular disease. Effective control of postprandial hyperglycaemia is therefore important for reducing this risk. Some flavonoids are known to inhibit intestinal a-glucosidase and pancreatic a-amylase. The aim of this study was to derive a Quantitative Structure-Activity Relationship (QSAR) analysis for a-glucosidase inhibition potential of 18 flavonoids. Two-dimensional (2D), three- dimensional (3D) molecular descriptors, quantum chemical descriptors, and physicochemical parameters, derived from optimized three- dimensional structure, have been calculated applying the PCLIENT (an on-line version of Dragon program) and HyperChem 8.0. Indicator variables, that mark the number and position of OH groups in flavonoid molecule, also have been included in QSAR analysis. Multiple regression analysis was performed using STATISTICA 7.0. Selection of predictor variables for multiple regression was performed by best-subset method. Best-developed bi-parametric (r2=0.80 ; F=30.35) and tri-parametric (r2=0.84 ; F=25.42) QSAR models are consisted of: indicator variables, 3D-MoRSE, topological, and GETAWEY descriptors. The obtained models demonstrated a positive influence of hydroxylation at the 4'- position and number of electronegative atoms in the molecule on inhibitory activity of studied compounds. Size and shape of the molecule, as well as three-dimensional charge distribution inside of molecule also play an important role in inhibition of a-glucosidase by flavonoids. Presented QSAR could be a useful for the design of new molecules more efficient in inhibition of enzymes responsible for the glucose production from carbohydrates.

QSAR ; flavonoids ; inhibition ; a-glucosidase ; diabetes

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