ADME, Toxicity, Molecular Docking, Molecular Dynamics, Glucokinase activation, DPP‐IV, α‐amylase, and α‐glucosidase Inhibition Assays of Mangiferin and Friedelin for Antidiabetic Potential

Abstract

Today the alarming situation of diabetes seeks innovative antidiabetic medications, especially those derived from natural sources,as natural substances are safer than manufactured pharmaceuticals. Therefore, this study investigated the inhibitory propertiesof mangiferin and friedelin against glucokinase (GK), dipeptidyl peptidase-IV (DPP-IV), α-amylase, and α-glucosidase usingcomputational methods, in vitro enzyme assays, and in-depth ADMET analysis. The study utilized a computer-aided drug designapproach to assess the potential therapeutic properties of mangiferin and friedelin as Type 2 diabetes mellitus (T2DM) therapeuticagents. Molecular docking studies’ outcomes encouraged the evaluation of both compounds in in vitro enzymatic assays. Thedocking study results were validated with the help of molecular dynamics simulation. Mangiferin and friedelin showed that theyactivated GK 20% and 5% more than the basal activity of the enzyme, respectively. In the DPP-IV enzyme assay, mangiferin andfriedelin demonstrated IC50 values (74.93 ± 0.71 and 110.64 ± 0.21 μg/mL, respectively) comparable with the reference compoundsitagliptin. Moreover, mangiferin and friedelin showed IC 50 comparable to acarbose against α-amylase (9.72 ± 0.15, 11.84 ± 0.06, and10.19 ± 0.05 mg/mL, respectively). In the α-glucosidase enzyme assay, mangiferin, friedelin, and acarbose displayed 11.72 ± 0.10,14.34 ± 0.02, and 9.14 ± 0.06 mg/mL of IC50 values, respectively. The compounds showed promising in silico ADMET and drug-likeness properties, with potential binding affinities with all enzymes. In vitro enzymatic assays showed mangiferin and friedelin activated GK 20% and 5% more than basal activity, with IC50 values comparable to acarbose