A study on flavanomarein as a potential natural SGLT2 inhibitor through molecular docking

Sodium-glucose cotransporter 2 (SGLT2) is a well-recognized drug target for type 2 diabetes mellitus (T2DM) with distinctive therapeutic advantages, as its insulin-independent hypoglycemic mechanism breaks the limitations of traditional antidiabetic therapies. Classic hypoglycemic agents such as metformin and sulfonylureas play an irreplaceable role in clinical practice, yet some patients suffer from poor curative effect, drug tolerance and adverse reactions like hypoglycemia, which cannot satisfy the demand of individualized treatment. China abounds in natural medicinal resources, and traditional Chinese medicines (TCMs) and natural products have emerged as important resources for developing novel SGLT2 inhibitors due to their unique merits of multi-target function and low toxicity, while their inhibitory mechanisms against SGLT2 remain insufficiently investigated. There is an urgent need to explore efficient and low-toxic natural inhibitors and clarify their molecular mechanisms. This study aimed to determine the binding ability, interaction mode, and potential of flavanomarein (a naturally occurring flavonoid) as a potential natural SGLT2 inhibitor. Two molecular docking tools, AutoDock Vina and LeDock, were used to compare the binding characteristics of flavanomarein with 24 known SGLT2 inhibitors. The results indicated that the binding affinity of flavanomarein to SGLT2 was -9.196 kcal/mol, ranking 4th among the 25 compounds in the AutoDock Vina scoring. Its binding was mediated mainly by hydrogen bonds (with Asp158 and His80 among the most frequent contact residues) and by π–π stacking involving Tyr290, showing a binding mechanism consistent with that of FDA approved SGLT2 inhibitors. In addition, Phe206, which lies on transmembrane helix 5 outside the orthosteric pocket, was examined by computational site-directed mutagenesis: four single-point variants (F206A, F206Y, F206W and F206L) and the wild-type receptor were re-docked under identical conditions, and none of the four substitutions changed the predicted binding free energy beyond the noise of the scoring function (|ΔΔG| < 0.5 kcal/mol), indicating that this residue does not contribute to ligand binding. ADMET prediction indicated favourable intestinal absorption and no predicted hERG blockade, but also identified hepatic and mutagenicity alerts that warrant experimental follow-up. These findings support the feasibility of flavanomarein as a potential natural SGLT2 inhibitor and provide a molecular basis for its further development as a SGLT2-targeted agent.