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Nano-ellagic acid: inhibitory actions on aldose reductase and α-glucosidase in secondary complications of diabetes, strengthened by in silico docking studies.

ABSTRACT: Increased blood sugar levels in prolonged diabetes lead to secondary complications such as retinopathy, neuropathy, and nephropathy, which gradually end in death. Synthesis of nano-phytomedicines from active phytoconstituents for novel emerging applications in the field of pharmaceuticals is of huge interest among researchers. In the present investigation, encapsulated ellagic acid (NEA) was synthesized at four different concentrations (0.2%, 0.3%, 0.4%, 0.5%) using ZnO nanoparticles as encapsulating agent. The surface morphology (fiber-like structures) of the nanoparticles were determined by scanning electron microscopy (SEM) and particle size (161-297 nm) and zeta potential (- 54.9-38.4 mV) were determined by dynamic light scattering technique. Further, the α-glucosidase and aldose reductase enzymes were significantly inhibited by the 0.4% of NEA compared to the other concentrations which strengthened our studies in overcoming the secondary complications of diabetes. The interaction analysis between ellagic acid and insulin receptor found Hit 1 among 10 executed ∆G score and energy of - 5.76, - 4.63 kcal/mol and formed polar bond with Arg 113 with - 1.175 Å distance. The residues Arg115, Lys116, Phe118, Ile115, Arg1131, Arg1155, Ile1157, Lys1165 and Phe1186 were found in ligand-protein interactions. ADME/T analysis of hit 1 was within the acceptable range without any toxic functional groups, providing a framework for developing novel therapeutics.

SUBMITTER: Marella S

PROVIDER: S-EPMC7498530 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Nano-ellagic acid: inhibitory actions on aldose reductase and α-glucosidase in secondary complications of diabetes, strengthened by <i>in silico</i> docking studies.

Marella Saritha S Hema Kanipakam K Shameer Syed S Prasad T N V K V TNVKV

3 Biotech 20200917 10

Increased blood sugar levels in prolonged diabetes lead to secondary complications such as retinopathy, neuropathy, and nephropathy, which gradually end in death. Synthesis of nano-phytomedicines from active phytoconstituents for novel emerging applications in the field of pharmaceuticals is of huge interest among researchers. In the present investigation, encapsulated ellagic acid (NEA) was synthesized at four different concentrations (0.2%, 0.3%, 0.4%, 0.5%) using ZnO nanoparticles as encapsul ...[more]

PMID: 32999815

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Project description:Diabetes mellitus is a chronic disease that is becoming a serious global health problem. Diabetes has been considered to be one of the major risks of cataract and retinopathy. Synthetic and natural product inhibitors of carbohydrate degrading enzymes are able to reduce type 2 diabetes and its complications. For a long time, potatoes have been portrayed as unhealthy for diabetic patients by some nutritionist due to their high starch content. However, purple and red potato cultivars have received considerable attention from consumers because they have high levels of polyphenolic compounds that have potent antioxidant activities. In this study, we screened the total phenolics (TP) and total anthocyanins (TA) and analyzed the phenolic and anthocyanin compounds in selected potato cultivars and advanced selections with distinct flesh colors (purple, red, yellow and white). Purple and red potato cultivars had higher levels of TP and TA than tubers with other flesh colors. Chlorogenic acid is the predominant phenolic acid, and major anthocyanin is composed of the derivatives of petunidin, peonidin, malvidin and pelargonidin. We tested the potential inhibitory effect of potato extracts on the activities of α-amylase and α-glucosidase, which were targeted to develop antidiabetic therapeutic agents. We also measured inhibitory effect of potato extracts on aldose reductase (AR) which is a key enzyme that has been a major drug target for the development of therapies to treat diabetic complications. Purple flesh tubers extract showed the most effective inhibition of α-amylase, α-glucosidase, and aldose reductase with IC50 values 25, 42, and 32 μg/ml, respectively. Kinetic studies showed that anthocyanins are noncompetitive inhibitors of these enzymes, whereas phenolic acids behaved as mixed inhibitors for α-amylase and α-glucosidase and noncompetitive inhibitors for AR. This study supports the development of a positive and healthful image of potatoes, which is an important issue for consumers.

Project description:BackgroundDiabetes remains a leading cause of morbidity and mortality due to various complications induced by hyperglycemia. Inhibiting Aldose Reductase (AR), an enzyme that converts glucose to sorbitol, has been studied to prevent long-term diabetic consequences. Unfortunately, drugs targeting AR have demonstrated toxicity, adverse reactions, and a lack of specificity. This study aims to explore African indigenous compounds with high specificity as potential AR inhibitors for pharmacological intervention.MethodologyA total of 7,344 compounds from the AfroDB, EANPDB, and NANPDB databases were obtained and pre-filtered using the Lipinski rule of five to generate a compound library for virtual screening against the Aldose Reductase. The top 20 compounds with the highest binding affinity were selected. Subsequently, in silico analyses such as protein-ligand interaction, physicochemical and pharmacokinetic profiling (ADMET), and molecular dynamics simulation coupled with binding free energy calculations were performed to identify lead compounds with high binding affinity and low toxicity.ResultsFive natural compounds, namely, (+)-pipoxide, Zinc000095485961, Naamidine A, (-)-pipoxide, and 1,6-di-o-p-hydroxybenzoyl-beta-d-glucopyranoside, were identified as potential inhibitors of aldose reductase. Molecular docking results showed that these compounds exhibited binding energies ranging from -12.3 to -10.7 kcal/mol, which were better than the standard inhibitors (zopolrestat, epalrestat, IDD594, tolrestat, and sorbinil) used in this study. The ADMET and protein-ligand interaction results revealed that these compounds interacted with key inhibiting residues through hydrogen and hydrophobic interactions and demonstrated favorable pharmacological and low toxicity profiles. Prediction of biological activity highlighted Zinc000095485961 and 1,6-di-o-p-hydroxybenzoyl-beta-d-glucopyranoside as having significant inhibitory activity against aldose reductase. Molecular dynamics simulations and MM-PBSA analysis confirmed that the compounds bound to AR exhibited high stability and less conformational change to the AR-inhibitor complex.ConclusionThis study highlighted the potential inhibitory activity of 5 compounds that belong to the African region: (+)-Pipoxide, Zinc000095485961, Naamidine A, (-)-Pipoxide, and 1,6-di-o-p-hydroxybenzoyl-beta-d-glucopyranoside. These molecules inhibiting the aldose reductase, the key enzyme of the polyol pathway, can be developed as therapeutic agents to manage diabetic complications. However, we recommend in vitro and in vivo studies to confirm our findings.

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Nano-ellagic acid: inhibitory actions on aldose reductase and α-glucosidase in secondary complications of diabetes, strengthened by in silico docking studies.

Publications

Nano-ellagic acid: inhibitory actions on aldose reductase and α-glucosidase in secondary complications of diabetes, strengthened by <i>in silico</i> docking studies.

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