Inhibition Kinetics and Theoretical Studies on Zanthoxylum chalybeum Engl. Dual Inhibitors of α-Glucosidase and α-Amylase

Abstract

Compounds from <i>Zanthoxylum chalybeum</i> Engl. were previously reported for inhibitory activities of amylase and glucosidase enzymatic action on starch as a preliminary study toward the establishment of a management strategy against postprandial hyperglycemia, however, the inhibitory kinetics and molecular interaction of these compounds were never established. A study was thus designed to establish the inhibitory kinetics and in silico molecular interaction of α-glucosidase and α-amylase with <i>Z. chalybeum</i> metabolites based on Lineweaver-Burk/Dixon plot analyses and using Molecular Operating Environment (MOE) software, respectively. Skimmianine (<b>5</b>), Norchelerythrine (<b>6</b>), 6-Acetonyldihydrochelerythrine (<b>7</b>), and 6-Hydroxy-N-methyldecarine (<b>8</b>) alkaloids showed mixed inhibition against both α-glucosidase and α-amylase with comparable <i>K_i</i> to the reference acarbose (<i>p</i> > 0.05) on amylase but significantly higher activity than acarbose on α-glucosidase. One phenolic 2,3-Epoxy-6,7-methylenedioxyconiferol (<b>10</b>) showed a competitive mode of inhibition both on amylase and glucosidase which were comparable (<i>p</i> > 0.05) to the activity of acarbose. The other compounds analyzed and displayed varied modes of inhibition between noncompetitive and uncompetitive with moderate inhibition constants included chaylbemide A (<b>1</b>), chalybeate B (<b>2</b>) and chalybemide C (<b>3</b>), fagaramide (<b>4</b>), ailanthoidol (<b>9</b>), and sesame (<b>11</b>). The important residues of the proteins α-glucosidase and α-amylase were found to have exceptional binding affinities and significant interactions through molecular docking studies. The binding affinities were observed in the range of -9.4 to -13.8 and -8.0 to -12.6 relative to the acarbose affinities at -17.6 and -20.5 kcal/mol on α-amylase and α-glucosidase residue, respectively. H-bonding, π-H, and ionic interactions were noted on variable amino acid residues on both enzymes. The study thus provides the basic information validating the application of extracts of <i>Z. chalybeum</i> in the management of postprandial hyperglycemia. Additionally, the molecular binding mechanism discovered in this study could be useful for optimizing and designing new molecular analogs as pharmacological agents against diabetes.