The Inhibitory Effects of Nucleosides, Nicotinamide Adenine Dinucleotide, Adenosine 5'-Triphosphate, Inosine, Nicotinamide Riboside and Nicotinamide Mononucleotide Against α-Amylase and α-Glucosidase Enzymes

Abstract

Diabetes is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. Inhibition of carbohydrate hydrolyzing enzymes leads to decrease in the absorption of glucose which is considered as one of the effective managements of diabetes mellitus. Vegetable, fruit, milk and fish are good sources of nucleosides and inosine (INO), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) with versatile health benefits. The well-adapted structural features of these compounds for the inhibition/activation of enzymes include several available hydrogen bond (H-bond) acceptors and donors, flexible backbone and hydrophobic nature. The substrates of α-amylase (α-Amy) and α-Glucosidase (α-Glu), known as key absorbing enzymes, have functional groups (OH groups) resembling nucleosides. Therefore, the present study was conducted to evaluate the inhibitory properties of nucleosides against αAmy and α-Glu. The median inhibition concentration (IC50) values for α-Glu in the presence of adenosine (ADN), adenosine triphosphate (AMP), NR, INO, adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), Adenosine diphosphate (ADP)-ribose, ADP-glucose and NMN were determined 208.6±3.8, 254.1±5.2, 177.7±4.8, 192.1±5.2, 215.9±2.7, 65.4±1.3, 63.4±2.2, 75.6±4.2 and 196.1±2.6, respectively. The IC50 values α-Amy in the presence of ADN, AMP, NR, INO, ATP, NAD, ADP-ribose, ADP-glucose and NMN were determined 145.3±2.4, 202.3±3.9, 127.7±4.8, 163.5±3.6, 185.3±1.2, 80.4±2.8, 64.8±4.7, 51.1±1.6 and 166.5±1.4, respectively. Moreover, the Ki values of NAD were calculated as 13.8±0.8 and 18.6±2.4 µM for α-Glu and α-Amy in a competitive-mode and noncompetitive -mode inhibition. In addition, to communicate with the active site of α-Glu and α-Amy respectively, NR presented a binding energy of -7.8 and -6.8 kcal/mol, INO -7.3 and -6.9, ATP -8.3 and -7.3, NAD -10.0 and -8.5, ADP-ribose -8.7 and -7.4, ADP-glucose -8.9 and -7.6, cAMP -6.6 and -6.3 and NMN -6.8 and -7.0 kcal/mol. These antioxidant inhibitors may be potential anti-diabetic drugs, not only to reduce glycemic index, but also to limit the activity of the major reactive oxygen species (ROS) producing pathways. Key words: Nucleosides, NAD, hydrolyzing enzymes, enzyme inhibition, hyperglycemia