The activity of glycogen phosphorylase (GP) plays a crucial role in regulating glycogen metabolism, and its excessive activity has been closely linked to the pathogenesis of metabolic disorders, such as type 2 diabetes (T2D). Therefore, targeting GP inhibition has emerged as a significant therapeutic strategy for managing this disease. Current research focuses on the discovery and development of novel small molecules capable of suppressing GP activity. Among these, flavonoids have gained considerable attention for their remarkable inhibitory potential. In this study, we propose isocoreopsin, a naturally occurring, water-soluble, edible compound extracted from the flower petals of Butea monosperma, as a promising GP inhibitor. Preliminary molecular docking analyses revealed that isocoreopsin exhibited the lowest binding free energy compared to several other potential inhibitory molecules, indicating a strong and stable interaction with GP. These findings underscore its potential efficacy in modulating GP activity and suggest that isocoreopsin may serve as a valuable candidate for further in vivo investigations. Given its favorable binding properties and natural origin, we recommend that animal model studies be conducted to validate its therapeutic potential in the management of T2D. These studies could pave the way for developing safe, plant-derived treatments aimed at better glycemic control in diabetic patients.

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1. Chetter BA, Kyriakisb E, Barra D, et al. Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors. Bioorg Chem. 2020;102:104003.
2. Agiua L. Physiological control of liver glycogen metabolism: lessons from novel glycogen phosphorylase inhibitors. J Biochem. 2010;10(12).
3. Henke BR, Sparks SM. Glycogen phosphorylase inhibitors. Curr Top Med Chem. 2006;6(8):845–857.
4. Gardiner TA, Canning P, Tipping N, et al. Abnormal glycogen storage by retinal neurons in diabetes. Invest Ophthalmol Vis Sci. 2015;56:8008–8018.
5. Oikonomakos NG, Somsák L. Advances in glycogen phosphorylase inhibitor design. Curr Opin Drug Discov Devel. 2008;9(4):379–395.
6. Awad TA, Alfatih F, Shafiq M, et al. Evaluation of chalcones as new glycogen phosphorylase inhibitors – an in-vitro and in-silico approach. Nat Prod Res. 2014;1–8.
7. 2D Structure of Compound 193124 [Online]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/193124#section=2D-Structure
8. RCSB PDB. Structure of 6Y55 [Online]. Available from: https://www.rcsb.org/structure/6y55
9. Irfan N, Vaithyanathan P, Anandaram H, et al. Active and allosteric site binding molecular mechanics-quantum mechanics studies of stevioside derivative in PCSK9 protein intended to provide a safe antilipidemic agent. bioRxiv [Preprint]. 2023. doi:10.1101/2023.05.04.539221.
10. Vaithyanathan P. Analysis of an insilico interaction by a curcumin derivative specially only with the AKT1 molecule but not AKT2. Research Square [Preprint]. 2023. doi:21203/rs.3.rs-3156936/v1.
11. Vaithyanathan P. Insilico analysis of an interaction between an endogenous peptide fragment of NUR77 receptor from human cells and USAG1 protein - may induce teeth regeneration. Research Square [Preprint]. 2024. doi:10.21203/rs.3.rs-4193367/v1.

The activity of glycogen phosphorylase (GP) plays a crucial role in regulating glycogen metabolism, and its excessive activity has been closely linked to the pathogenesis of metabolic disorders, such as type 2 diabetes (T2D). Therefore, targeting GP inhibition has emerged as a significant therapeutic strategy for managing this disease. Current research focuses on the discovery and development of novel small molecules capable of suppressing GP activity. Among these, flavonoids have gained considerable attention for their remarkable inhibitory potential. In this study, we propose isocoreopsin, a naturally occurring, water-soluble, edible compound extracted from the flower petals of Butea monosperma, as a promising GP inhibitor. Preliminary molecular docking analyses revealed that isocoreopsin exhibited the lowest binding free energy compared to several other potential inhibitory molecules, indicating a strong and stable interaction with GP. These findings underscore its potential efficacy in modulating GP activity and suggest that isocoreopsin may serve as a valuable candidate for further in vivo investigations. Given its favorable binding properties and natural origin, we recommend that animal model studies be conducted to validate its therapeutic potential in the management of T2D. These studies could pave the way for developing safe, plant-derived treatments aimed at better glycemic control in diabetic patients.

🔒 This is a subscription article

Full text is available to subscribers and institutional members. Please choose an option below to access it.

1. Chetter BA, Kyriakisb E, Barra D, et al. Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors. Bioorg Chem. 2020;102:104003.
2. Agiua L. Physiological control of liver glycogen metabolism: lessons from novel glycogen phosphorylase inhibitors. J Biochem. 2010;10(12).
3. Henke BR, Sparks SM. Glycogen phosphorylase inhibitors. Curr Top Med Chem. 2006;6(8):845–857.
4. Gardiner TA, Canning P, Tipping N, et al. Abnormal glycogen storage by retinal neurons in diabetes. Invest Ophthalmol Vis Sci. 2015;56:8008–8018.
5. Oikonomakos NG, Somsák L. Advances in glycogen phosphorylase inhibitor design. Curr Opin Drug Discov Devel. 2008;9(4):379–395.
6. Awad TA, Alfatih F, Shafiq M, et al. Evaluation of chalcones as new glycogen phosphorylase inhibitors – an in-vitro and in-silico approach. Nat Prod Res. 2014;1–8.
7. 2D Structure of Compound 193124 [Online]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/193124#section=2D-Structure
8. RCSB PDB. Structure of 6Y55 [Online]. Available from: https://www.rcsb.org/structure/6y55
9. Irfan N, Vaithyanathan P, Anandaram H, et al. Active and allosteric site binding molecular mechanics-quantum mechanics studies of stevioside derivative in PCSK9 protein intended to provide a safe antilipidemic agent. bioRxiv [Preprint]. 2023. doi:10.1101/2023.05.04.539221.
10. Vaithyanathan P. Analysis of an insilico interaction by a curcumin derivative specially only with the AKT1 molecule but not AKT2. Research Square [Preprint]. 2023. doi:21203/rs.3.rs-3156936/v1.
11. Vaithyanathan P. Insilico analysis of an interaction between an endogenous peptide fragment of NUR77 receptor from human cells and USAG1 protein - may induce teeth regeneration. Research Square [Preprint]. 2024. doi:10.21203/rs.3.rs-4193367/v1.