Flavones from Muntingia calabura leaves: structural elucidation and SAR for α-glucosidase inhibition by in vitro and in silico evaluation

Abstract

Phytochemical investigation of Muntingia calabura leaves led to the isolation of three new calaburones (1–3) and 12 known flavones (4–15). Their structures were elucidated by using advanced spectroscopic techniques and compared with existing literature. In vitro assay revealed that 12 out of the 15 flavones demonstrated potential α-glucosidase inhibitory activity compared to a positive control, acarbose. The three most potent compounds (3, 14, and 15), having IC₅₀ values of 5.4, 12.8, and 3.1 μM, respectively, were further investigated using molecular dynamics (MD) simulations to explore the structure–activity relationship (SAR) and assess their interactions with the α-glucosidase enzyme. The SAR analysis suggests that the presence of methoxy groups at C-3 and C-8, along with a hydroxyl group at C-5, plays a crucial role in the α-glucosidase inhibitory activity of these compounds. Molecular docking and molecular dynamics (MD) simulations show that these compounds form strong interactions with key amino acids of α-glucosidase, particularly hydrogen bonds and hydrophobic interactions, leading to the structural stability of the enzyme when bound with the ligand. Compound 15 exhibits the most substantial binding with α-glucosidase, primarily through interactions at the allosteric site, enhancing the stability of the enzyme–ligand complex. These results suggest compound 15 is the most promising candidate for development as an α-glucosidase inhibitor in anti-diabetic drug discovery.