Insight into potential anti-diabetic metabolites of Sycamore fig (Ficus sycomorus L.) across fruit development using metabolomics and molecular docking

Abstract

The metabolic profile, anti-diabetic activity, and bioactive metabolites of Ficus sycomorus L. (Sycamore fig) fruits were investigated across different developmental stages to identify potential candidates for diabetes management. UPLC/MS/MS analysis enabled the annotation of 52 compounds belonging to diverse chemical classes. Notably, unsaturated fatty acids were predominantly present in immature fruits but declined sharply as maturation commenced. Sugars were detected in the second mature stage, showing a substantial increase as fruits reached full ripeness. Alpha-amino acids and alkaloids were initially abundant in immature fruits, but their levels decreased with maturation. Interestingly, triterpenes were exclusively found in immature fruits, suggesting a stage-specific metabolic profile. OPLS-DA coefficient plots highlighted metabolites that distinguished the developmental stages, revealing patterns associated with anti-diabetic potential. Enzymatic assays demonstrated that all tested fruit samples exhibited significant inhibition of α-glycosidase and α-amylase activities. The immature fruit stage showed the strongest α-glycosidase inhibition (IC50 = 0.601 ± 0.05 µg/mL), whereas the fully ripe stage demonstrated the highest α-amylase inhibition (IC50 = 0.215 ± 0.007 µg/mL). Coefficients plots identified ten compounds positively correlated with anti-diabetic effects. Molecular docking was assessed on the ten identified metabolites, revealing rutin as the most potent α-amylase inhibitor with a score of −6.1 kcal/mol, while synephrine exhibited the highest stability against α-glycosidase (−6.7 kcal/mol). Synephrine, stearic acid, chlorogenic acid, and rutin, with the highest binding affinity to the anti-diabetic enzymes, were selected for further in-vitro assays, confirming their inhibitory activity against α-glycosidase or α-amylase. These findings position F. sycomorus fruits as promising natural sources of anti-diabetic agents, encouraging further research into their therapeutic potential.