Targeting aldose reductase using Natural African Compounds as Promising Agents for Managing Diabetic Complications

Miriam Eyram Lawson Gakpey ^1* Shadrack Arhin Aidoo ² Toheeb Jumah ^3* Siyabonga Msipa ⁴ Florence Mbaoji ⁵ Bukola Omonijo ⁶ Palesa Tjale ⁷ Mamadou Sangare ⁸ Hedia Tebourbi ⁹ George Hanson ¹⁰ Olaitan I. Awe ^11*

• ¹ Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
• ² Department of Virology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
• ³ School of Collective Intelligence, University Mohammed VI Polytechnic, Rabat, Morocco
• ⁴ Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Cape, South Africa
• ⁵ Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Nigeria, Nigeria
• ⁶ Department of Medical Laboratory Science, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology,, Ogbomosho, Nigeria
• ⁷ Department of Computational Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
• ⁸ International Center for Excellence in Research, Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Bamako Capital District, Mali
• ⁹ Department of Pathophysiology, Food and Biomolecules Laboratory, Higher Institute of Biotechnology of Sidi Thabet,, Sidi Thabet, Tunisia
• ¹⁰ Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
• ¹¹ African Society for Bioinformatics and Computational Biology, Cape Town, South Africa

Background: Diabetes 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. Methodology: A 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, insilico 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. Results: Five 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 interactionresults revealed that these compounds interacted with key inhibiting residues through hydrogen and hydrophobic interactionsand 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. Conclusion: This 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.