Elucidating the Glucokinase Activating Potentials of Naturally Occurring Prenylated Flavonoids: An Explicit Computational Approach

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.

In-silico Exploration of Phytoconstituents of Gymnema sylvestre as Potential Glucokinase Activators and DPP-IV Inhibitors for the future Synthesis of Silver Nanoparticles for the Treatment of Type 2 Diabetes Mellitus

Background: Diabetes has a large death toll worldwide, particularly as it falls into the ten leading causes of death. Type 2 diabetes mellitus (T2DM) occurs as the body becomes resistant to insulin and sugar accumulates in the blood. It has been observed that, dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucokinase activators are known therapeutic agents to treat T2DM. Among the possible medicinal plants, Gymnema sylvestre (GyS) belongs to the Apocynaceae family and is traditionally used for the treatment of different diseases. This plant is also known as 'Gurmur' because it has a sugar reducing ability. GyS was known to be one of the main botanicals for the treatment of diabetes. Objective: Rendering to the studies described above, we have tried to investigate the natural DPP-IV inhibitors and potent glucokinase activators from the phytoconstituents of GyS. New drug candidates from the medicinal plant GyS have been reported as potent DPP-IV inhibitors and glucokinase activators. Methods: As a preliminary investigation, we have studied the effectiveness of phytoconstituents of GyS in T2DM through molecular docking as a proof of concept of synthesizing silver nanoparticles (for the treatment of T2DM) using extract of this plant. Results: The present investigative research showed that diabetes mellitus has important values in the recognized compounds included in the present analysis. The nine compounds selected were evaluated on the basis of DPP-IV and glucokinase enzyme binding energy values and their drug properties. Except quercitol, all the selected compounds have exhibited very potent glucokinase activation potential than its native ligand. Gymnemasin A, lupeol, gymnemoside A, gymnemasaponin V and gymnemic acid I have shown excellent DPP-IV inhibitory potential. Conclusion: We are aiming to synthesis the silver nanoparticles of leaf extract of GyS for the treatment of T2DM. As a preliminary investigation, we have studied the effectiveness of phytoconstituents of GyS in T2DM through molecular docking as a proof of concept of synthesizing silver nanoparticles (for the treatment of T2DM) using extract of this plant. As a result of present investigation, it has been concluded that these compounds can be used to treat the T2DM and hence in future we will synthesize the silver nanoparticles of GyS extract for the treatment of T2DM.

Designing of some Novel Methyl 2-((4-(Benzamido)Phenyl)Sulfanyl)-1,2,3,4-tetrahydro-6-Methylpyrimidine-5-carboxylate Derivatives as Potential Glucokinase Activators through Molecular Docking

Aims: Glucokinase (GK) is a cytoplasmic enzyme that metabolizes the glucose to glucose- 6-phosphate and supports the adjusting of blood glucose levels within the normal range in humans. In pancreatic β-cells, it plays a leading role by governing the glucose-stimulated secretion of insulin and in liver hepatocyte cells, it controls the metabolism of carbohydrates. GK acts as a promising drug target for the treatment of patients with type 2 diabetes mellitus (T2DM). Study Design: In the current study, the goal is to identify new substituted benzamide derivatives and test them via molecular docking as possible anti-diabetic drugs. Place and Duration of Study: The present work has been carried out at S.N.J.B’s S.S.D.J. College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India during the time period of December-2020 to February-2021. Methodology: This work involved designing novel methyl 2-((4-(benzamido)phenyl)sulfanyl)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives and their screening by molecular docking studies to determine the binding interactions for the best-fit conformations in the binding site of the GK enzyme. Autodockvina 1.1.2 in PyRx 0.8 was used to perform the docking studies of all the designed novel derivatives and native ligand against the crystal structure of GK. Based on the results of docking studies, the selected molecules will be tested for their antidiabetic activity in the animal models. Results: Amongst the designed derivatives, compounds A2, A3, A8, A10, A11, A13, A14, A16, A17, and A18 have shown better binding free energy (between -8.7 to -10.3 kcal/mol) than the native ligand present in the enzyme structure. In present investigation, many molecules had formed strong hydrogen bond with Arg-63 which indicate the potential to activate GK. Conclusion: From above results it has been observed that these designed benzamide derivatives have potential to activate the human GK which enables us to proceed for the syntheses of these derivatives.