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

Abstract

Compounds from Zanthoxylum chalybeum 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 Z. chalybeum metabolites based on Lineweaver–Burk/Dixon plot analyses and using Molecular Operating Environment (MOE) software, respectively. Skimmianine (5), Norchelerythrine (6), 6-Acetonyldihydrochelerythrine (7), and 6-Hydroxy-N-methyldecarine (8) alkaloids showed mixed inhibition against both α-glucosidase and α-amylase with comparable Ki to the reference acarbose (p > 0.05) on amylase but significantly higher activity than acarbose on α-glucosidase. One phenolic 2,3-Epoxy-6,7-methylenedioxyconiferol (10) showed a competitive mode of inhibition both on amylase and glucosidase which were comparable (p > 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 (1), chalybeate B (2) and chalybemide C (3), fagaramide (4), ailanthoidol (9), and sesame (11). 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 Z. chalybeum 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.

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

“…These properties have been subjected to natural selection and evolutionary Pharmaceuticals 2024, 17, 510 2 of 19 processes, shaping their utility over hundreds of thousands of years. Consequently, they display a great variety of biological and therapeutic potentials spanning anti-tumor, antimicrobial, antiviral, antitripanosomal, α-Glucosidase inhibitory activity, and immunosuppressive actions to the inhibition of vascular smooth muscle contraction [4][5][6][7][8][9][10][11][12]. More than one-third of the drugs so far approved by the United States' Food and Drug Administration (FDA) are either derived from natural product precursors or are purely natural products [13][14][15].…”

Chemical composition by PTP 1B inhibitory activity guided analysis of plant-based antidiabetic polyherbal drug used in ethnomedical systems

“…The water is then orally taken periodically 3 times a day until the patient feels well. Z. chalybeum and X. stuhlmannii have been reported to exhibit antidiabetic activity as shown by inhibiting alpha amylase and glucosidase in previous studies (Agwaya et al 2016; Kimani et al 2013; Musabayane et al 2005). Despite the polyherbal drug being popular as antidiabetic remedies among many local people, little information is known about the chemical composition and the mode of action of the polyherbal drug.…”