Identifying high-efficiency α-glucosidase inhibitors from Abelmoschus manihot (L.) Medik. A quadrant-based integration of in vitro potency and in silico analysis

Context: α-Glucosidase represents one of the key treatments for diabetes based on its ability to regulate postprandial blood glucose levels. Aims: To evaluate the α-glucosidase inhibitory potential of Abelmoschus manihot (L.) Medik, an endemic species of Minahasa, Indonesia, which is consumed as a vegetable and has been used as an anti-diabetic herbal medicine. Methods: The α-glucosidase inhibitory activity of A. manihot ethanolic extract was benchmarked against acarbose in vitro. A multi-parametric quadrant analysis was applied to 27 identified phytochemicals to rank them based on binding affinity (ΔG) and ligand efficiency (LE). Top-ranked leads (stigmasterol and hibiscone-B) underwent 100 ns molecular dynamics (MD) simulations and MM-PBSA calculations to validate binding stability and energetic profiles. Results: The extract demonstrated robust, dose-dependent inhibition (IC50 = 1069.71 µg/mL) and achieved superior maximal efficacy (92.0%) compared to acarbose. Quadrant analysis identified stigmasterol as a "Power Binder" (ΔG = -9.17 kcal/mol) and hibiscone-B as a "Precision Lead" (LE = -0.43), both of which outperformed acarbose in atomic binding efficiency. MD simulations confirmed that hibiscone-B maintains a stable occupancy of the catalytic cleft, supported by persistent hydrogen bonds with ASP203 and ASP542. Conclusions: A. manihot serves as a potent botanical matrix for anti-diabetic leads. The narrow 3.5-fold potency gap between the crude extract and its pure lead, hibiscone-B, underscores the high efficiency of its phytochemical components, offering a superior alternative to traditional carbohydrate-mimetic inhibitors. Hibiscone-B and stigmasterol are identified as high-priority templates for the development of next-generation inhibitors.