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3. Exploration of Potent Human α‐Glucosidase Inhibitors Using In Silico Approaches: Molecular Docking, DFT, Molecular Dynamics Simulations, and MMPBSA.

Author

Bashyal, Jyoti, Raut, Bimal Kumar, Upadhyaya, Siddha Raj, Sharma, Kabita, Parajuli, Niranjan, and Rajkhowa, Sanchayita

Subjects
METABOLITES, MOLECULAR dynamics, MOLECULAR docking, DRUG development, BLOOD sugar
Abstract

Inhibiting α‐glucosidase, a key enzyme in carbohydrate hydrolysis, can potentially control diabetes mellitus. Although commercially available drugs effectively lower blood glucose levels to mitigate hyperglycemia, their associated gastrointestinal side effects necessitate the exploration of explicit inhibitors with minimal side effects. We studied a library of 80 secondary metabolites ascribed to their antidiabetic properties and screened the most potent inhibitors using a comprehensive in silico approach, including molecular docking, DFT study, MD simulation, PCA, MMPBSA calculation, and pharmacokinetic analysis. Scolopianate A and ponasterone A emerged as potent α‐glucosidase inhibitors, forming hydrogen bonds with the catalytic diad and exhibiting prominent binding affinities of −8 kcal/mol. Further analyses encompassed significant reactivity at the catalytic site and stable protein‐ligand complexes, as asserted by 100 ns RMSD, RMSF, Rg, SASA, H‐bond, and PCA‐based free energy landscape analysis. The subsequent analysis of MMPBSA indicating a higher binding free energy of these compounds compared to reference ligand, acarbose further strengthened the validity of these findings. Furthermore, drug‐like behavior and favorable ADMET profiles affirmed scolopianate A and ponasterone A as robust α‐glucosidase inhibitors. These findings highlight their promise for future drug development targeting α‐glucosidase inhibition in diabetes management; however, more research needs to be conducted. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Biochemical Analysis and Human Aldose Reductase Inhibition Activity of Selected Medicinal Plants of Nepal

Author

Upadhyaya, Siddha Raj, Magar, Lila Bahadur, Thapa, Ranjita, Joshi, Soniya, Khadayat, Karan, Marasini, Bishnu P., and Parajuli, Niranjan

Abstract

Aldose reductase has received extensive research as a key enzyme in the development of long-term problems linked to diabetes mellitus. Overexpression of this enzyme or with exceeded glucose concentration in the blood increases sorbitol on the retina leading to retinopathy, which is the adverse effect of type II diabetes. Approximately 100 million people are suffering from diabetic retinopathy globally. This research is focused on studying the total phenolic content (TPC), total flavonoid content (TFC), antioxidant potential, and aldose reductase inhibiting properties of selected medicinal plants such as Anacyclus pyrethrum, Bergenia ciliata, Rhododendron arboreum, and Swertia chirayita. In addition, ADMET analysis and molecular docking of seven previously identified compounds from the chosen medicinal plants were carried out against human aldose reductase (PDB ID: 4JIR). The ethanol extract of S. chirayita exhibited the highest TPC (4.63 ± 0.16 mg GAE/g) and TFC (0.90 ± 0.06 mg QE/g). Analysis of 2,2-diphenyl-1-picrylhydrazyl (DPPH)-based antioxidant assay showed that IC50 of the ethanolic extract of B. cilata and R. arboreum showed a significant antioxidant activity with IC50 value of 0.05 mg/mL. The percentage inhibition of AR by extract of B. ciliata (94.74 ± 0.01%) was higher than other plant extracts. A molecular docking study showed that morin isolated from B. ciliata showed a good binding interaction with AR. This study showed that the extracts of A. pyrethrum, B. ciliata, and R. arboreum could be potential sources of inhibitors against AR to treat retinopathy.

Published
2023
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7. Exploration of Potent Human a-Glucosidase Inhibitors Using In SilicoApproaches: Molecular Docking, DFT, Molecular Dynamics Simulations, and MMPBSA

Author

Bashyal, Jyoti, Raut, Bimal Kumar, Upadhyaya, Siddha Raj, Sharma, Kabita, Parajuli, Niranjan, and Rajkhowa, Sanchayita

Abstract

Inhibiting a-glucosidase, a key enzyme in carbohydrate hydrolysis, can potentially control diabetes mellitus. Although commercially available drugs effectively lower blood glucose levels to mitigate hyperglycemia, their associated gastrointestinal side effects necessitate the exploration of explicit inhibitors with minimal side effects. We studied a library of 80 secondary metabolites ascribed to their antidiabetic properties and screened the most potent inhibitors using a comprehensive in silicoapproach, including molecular docking, DFT study, MD simulation, PCA, MMPBSA calculation, and pharmacokinetic analysis. Scolopianate A and ponasterone A emerged as potent a-glucosidase inhibitors, forming hydrogen bonds with the catalytic diad and exhibiting prominent binding affinities of -8?kcal/mol. Further analyses encompassed significant reactivity at the catalytic site and stable protein-ligand complexes, as asserted by 100?ns RMSD, RMSF, Rg, SASA, H-bond, and PCA-based free energy landscape analysis. The subsequent analysis of MMPBSA indicating a higher binding free energy of these compounds compared to reference ligand, acarbose further strengthened the validity of these findings. Furthermore, drug-like behavior and favorable ADMET profiles affirmed scolopianate A and ponasterone A as robust a-glucosidase inhibitors. These findings highlight their promise for future drug development targeting a-glucosidase inhibition in diabetes management; however, more research needs to be conducted.

Published
2024
Full Text
View/download PDF

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