Glucokinase activators are considered as new therapeutic arsenals that bind to the allosteric activator sites of glucokinase enzymes, thereby maximizing its catalytic rate and increasing its affinity to glucose. This study was designed to identify potent glucokinase activators from prenylated flavonoids isolated from medicinal plants using molecular docking, molecular dynamics simulation, density functional theory, and ADMET analysis. Virtual screening was carried out on glucokinase enzymes using 221 naturally occurring prenylated flavonoids, followed by molecular dynamics simulation (100 ns), density functional theory (B3LYP model), and ADMET (admeSar 2 online server) studies. The result obtained from the virtual screening with the glucokinase revealed arcommunol B (−10.1 kcal/mol), kuwanon S (−9.6 kcal/mol), manuifolin H (−9.5 kcal/mol), and kuwanon F (−9.4 kcal/mol) as the top-ranked molecules. Additionally, the molecular dynamics simulation and MM/GBSA calculations showed that the hit molecules were stable at the active site of the glucokinase enzyme. Furthermore, the DFT and ADMET studies revealed the hit molecules as potential glucokinase activators and drug-like candidates. Our findings suggested further evaluation of the top-ranked prenylated flavonoids for their in vitro and in vivo glucokinase activating potentials.

Diabetes mellitus is a life-threatening non-communicable disease that affects all age groups. Despite the increased attention it has received in recent years, the number of diabetic patients has grown exponentially. These increased cases are attributed to essential enzymes involved in blood glucose regulation. In this study, we attempt to reveal the aldose reductase inhibitory potential of xanthones isolated from African medicinal plants. Ensemble docking, molecular dynamics simulation, density functional theory (DFT), and ADMET methods were employed to identify drug candidates as aldose reductase inhibitors. The ensemble docking results identified mangostenone B, bangangxanthone A, smeathxanthone B, mangostenone A, and allanxanthone B as potent inhibitors against the aldose reductase enzyme. Molecular dynamics studies showed the xanthones established better binding mode and affinities against the enzyme. Moreover, the electronic properties of the xanthones explained their good pharmacological potentials. Therefore, our findings suggest that the hit molecules be investigated in vitro and in vivo for drug development against aldose reductase.

Background: Type 2 diabetes mellitus continues to pose a threat to the existence of the human race. The increasing number of diabetic subjects can be effectively controlled by targeting enzymes responsible for high blood glucose levels. Xanthones are a class of phytochemicals that possesses promising pharmacological potentials. Objective: This study identified fructose 1,6-biphosphatase (FBPase) inhibitors by exploring xanthones isolated from African medicinal plants through ensemble docking, molecular dynamics simulation and density functional theory methods. Methods: The study used ensemble docking, molecular dynamics simulation and density functional theory (B3LYP/6-3G (d,p) basis set) and ADMET methods to select lead compound that may be effective as fructose-I,6-biphosphatase inhibitor. Results: The ensemble docking results identified globulixanthone C (-10.0 kcal/mol), 1-Isomangostin (-9.0 kcal/mol), laurentixanthone A (-9.0 kcal/mol), bangangxanthone A (-8.9 kcal/mol) and staudtiixanthone B (-8.8 kcal/mol) as potential inhibitors of fructose-1,6-biphosphatase. Molecular dynamics studies showed the xanthones established good binding mode and their binding energy ranged from -74.057 to 53.669 kJ/mol. Also, the electronic and ADMET studies of the xanthones elucidated their excellent pharmacological potential. Conclusion: The study identified xanthones as potential fructose-1,6-biphosphatase inhibitors. The ligands' binding energy and MMPBSA calculations supported their possible inhibitory property. Also, the ADMET properties estimated show the ligands as suitable drug candidates as fructose-1,6-biphosphatase inhibitors. Further in vitro and in vivo investigation of the hit molecules is necessary to develop new FBPase inhibitors.