Uncovering Potential Novel Antidiabetic Compounds from African Traditional Medicinal Plants: A Computer-Aided Study

Background: The prevalence of type 2 diabetes mellitus (T2DM) has increased markedly in recent years. Although traditional medicinal plants and natural products offer promising candidates for antidiabetic drugs, their full potential remains largely underexplored. Objectives: This study aimed to identify antidiabetic phytocompounds from a database of African plant-derived compounds, which were screened against four key antidiabetic targets: alpha-amylase 1 (AMY1A), α-glucosidase (MGAM), Protein Tyrosine Phosphatase 1B (PTP1B), and dipeptidyl peptidase IV (DPP-IV). Methods: The compounds were initially filtered for drug-likeness and subsequently screened using molecular docking. The top candidates underwent molecular dynamics (MD) simulations. During these simulations, the binding energies were calculated using the Molecular Mechanics Generalized Born Surface Area (MMGBSA) method. Additionally, several structural parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (rGyr), polar surface area (PSA), molecular surface area (MolSA), and solvent accessible surface area (SASA) were analyzed. Results: A total of 43 unique compounds belonging to several chemical classes (i.e., flavonoids, terpenoids, alkaloids, iridoids, and xanthones) were identified, exhibiting docking scores comparable to known controls. The results were as follows: docking scores of -7.4 to -8.7 kcal/mol (control: -9.7) for AMY1A, -6.8 to -8.0 kcal/mol (control: -8.2) for MGAM, -8.1 to -9.6 kcal/mol (control: -9.3) for DPP4, and -5.9 to -6.8 kcal/mol (control: -9.1) for PTP1B. MD simulations indicated that AMY1A-101679366 and DPP4-393472 complexes are negative and notably lower (-65.3 kcal/mol and -54.1 kcal/mol, respectively) than their respective controls. Furthermore, the MD simulations revealed relatively stable RMSD and RMSF profiles for the complexes, with fluctuations below 2.0 Å. The rGyr, PSA, MolSA, and SASA analyses further confirmed the stability of the protein-ligand complexes. Conclusion: The findings unveiled several compounds with promising antidiabetic potential, establishing a basis for further in vitro and in vivo studies to explore their therapeutic applications in T2DM treatment. Additionally, these compounds may serve as scaffolds for enhanced drug development.