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

Phytochemical investigation of <i>Muntingia calabura</i> 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. <i>In vitro</i> 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.