Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complications
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 h...
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Frontiers Media S.A.
2025-02-01
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| author | Miriam E. L. Gakpey Shadrack A. Aidoo Toheeb A. Jumah George Hanson Siyabonga Msipa Florence N. Mbaoji Omonijo Bukola Palesa C. Tjale Mamadou Sangare Hedia Tebourbi Olaitan I. Awe |
| author_facet | Miriam E. L. Gakpey Shadrack A. Aidoo Toheeb A. Jumah George Hanson Siyabonga Msipa Florence N. Mbaoji Omonijo Bukola Palesa C. Tjale Mamadou Sangare Hedia Tebourbi Olaitan I. Awe |
| author_sort | Miriam E. L. Gakpey |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-cfe665b5d8224ca38b2602c5269e158d |
| institution | Kabale University |
| issn | 2673-7647 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Bioinformatics |
| spelling | doaj-art-cfe665b5d8224ca38b2602c5269e158d2025-02-10T10:42:16ZengFrontiers Media S.A.Frontiers in Bioinformatics2673-76472025-02-01510.3389/fbinf.2025.14992551499255Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complicationsMiriam E. L. Gakpey0Shadrack A. Aidoo1Toheeb A. Jumah2George Hanson3Siyabonga Msipa4Florence N. Mbaoji5Omonijo Bukola6Palesa C. Tjale7Mamadou Sangare8Hedia Tebourbi9Olaitan I. Awe10Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, GhanaDepartment of Virology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, GhanaSchool of Collective Intelligence, University Mohammed VI Polytechnic, Rabat, MoroccoDepartment of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, GhanaDepartment of Integrative Biomedical Science, Faculty of Health Sciences, University of Cape Town, Cape Town, South AfricaDepartment of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu, NigeriaDepartment of Medical Laboratory Science, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomosho, Oyo, NigeriaDepartment of Computational Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South AfricaAfrican Center of Excellence in Bioinformatics (ACE-B), University of Science, Techniques and Technologies of Bamako (USTTB), Bamako, Mali0Pathophysiology, Food and Biomolecules Laboratory, Higher Institute of Biotechnology of Sidi Thabet, Sidi Thabet, Tunisia1African Society for Bioinformatics and Computational Biology, Cape Town, South AfricaBackgroundDiabetes 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.https://www.frontiersin.org/articles/10.3389/fbinf.2025.1499255/fulldiabetes mellitusaldose reductasemolecular dockingpharmacokineticsmolecular dynamics simulations |
| spellingShingle | Miriam E. L. Gakpey Shadrack A. Aidoo Toheeb A. Jumah George Hanson Siyabonga Msipa Florence N. Mbaoji Omonijo Bukola Palesa C. Tjale Mamadou Sangare Hedia Tebourbi Olaitan I. Awe Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complications Frontiers in Bioinformatics diabetes mellitus aldose reductase molecular docking pharmacokinetics molecular dynamics simulations |
| title | Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complications |
| title_full | Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complications |
| title_fullStr | Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complications |
| title_full_unstemmed | Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complications |
| title_short | Targeting aldose reductase using natural African compounds as promising agents for managing diabetic complications |
| title_sort | targeting aldose reductase using natural african compounds as promising agents for managing diabetic complications |
| topic | diabetes mellitus aldose reductase molecular docking pharmacokinetics molecular dynamics simulations |
| url | https://www.frontiersin.org/articles/10.3389/fbinf.2025.1499255/full |
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